Clinical trial NCT04782856
Conditions: Thyroid Goiter Hypothyroidism Thyroid Cancer
Sponsor: Virginia Commonwealth University
Start date: 2020-10-28; Completion date: 2023-04-19
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this research study is to measure the changes in energy metabolism (how the body burns energy), cardiovascular function (heart function), and lipid metabolism (cholesterol break down and building) before and after thyroidectomy (surgical removal of thyroid gland) in response to two approved therapies for hypothyroidism: levothyroxine (LT4) or Liothyronine/levothyroxine (LT3/LT4) combination therapy.

Detailed description:
In this study, Levothyroxine (LT4) and placebo (a look-alike inactive substance, a "sugar pill") will be compared to Liothyronine/ Levothyroxine (LT3/LT4) combination therapy.

Levothyroxine LT4 and Liothyronine (LT3) are drugs approved by the U. S. Food and Drug Administration (FDA).

All participants will be required follow VCU Health COVID-19 standard of Care screening procedures.

This study requires approximately five study visits The five-study visits required will be a Screening Visit (outpatient), one Baseline Visit, (inpatient) one Six Week Visit, (outpatient), one Three Month Visit and one Six Month Visit (both inpatient). A COVID-19 test will be done 48 hours (2 days) before each of the three-inpatient visit, Baseline Visit, Three Month and Six Month Visit.

Participants will be asked to:

1. Give permission for the researchers to collect information about their medical history from participants and their medical records five times during the study visits and for 5 years after the study visits.
2. Have a Physical exam done 5 times
3. 24-hour energy expenditure recording in the Whole room indirect calorimeter studies 3 times (inpatient overnight stays: Baseline, Three months, and Six months visits)
4. Study drug will be dispensed three times
5. Have study drug dose adjustments two times
6. Genomic blood draw for DNA one time
7. Have blood drawn five times
8. Have an DXA Scan two times
9. Have an Echocardiogram three times
10. Complete questionnaire three times
11. Have Accelerometers sensors laced 3 times (inpatient overnight stays: Baseline, Three months, and Six months visits)
12. ClearSight (blood pressure monitoring) procedure three times
13. Be randomized to take either Levothyroxine LT4 + placebo group or LevothyroxineLT3/Liothyronine LT4 group from baseline through 6 months

Participation in this study will last up to 6 months after surgery. Approximately 30 total individuals will participate in this study

Arms: arm 1: Levothyroxine (LT4) and placebo (a look-alike inactive substance, a "sugar pill") Patients in the LT4 group will be started at a dose of 1.6 mcg/Kg (52 The VCU Investigational Pharmacy will over-encapsulate LT4 plus placebo, in "AM" and "PM" color coded capsules. Patients will be instructed to take the AM drug first thing in the morning with water only, and to wait at least 30 minutes before taking other medications coffee or breakfast. The PM dose will be taken at least 30 minutes before dinner. Dose adjustments will be performed at the 6-week and 3-month follow up visits by an unblinded endocrinologist (Dr. Yavuz) aiming to achieve and maintain a target TSH within the normal range and within ± 0.5 mcIU/ml from the baseline (pre-surgery) TSH, Doses will be rounded to the nearest available formulation. arm 2: Liothyronine/levothyroxine (LT3/LT4) combination therapy. LT4/LT3 group will have 25 mcg of LT4 substituted with 5 mcg LT3 twice daily, to mimic the average daily T3 production form the thyroid The VCU Investigational Pharmacy will over-encapsulate LT4 plus 5 mcg LT3 in "AM" and "PM" color coded capsules. Patients will be instructed to take the AM drug first thing in the morning with water only, and to wait at least 30 minutes before taking other medications coffee or breakfast. The PM dose will be taken at least 30 minutes before dinner. Dose adjustments will be performed at the 6-week and 3-month follow up visits by an unblinded endocrinologist (Dr. Yavuz) aiming to achieve and maintain a target TSH within the normal range and within ± 0.5 mcIU/ml from the baseline (pre-surgery) TSH, Doses will be rounded to the nearest available formulation. No changes will be made in LT3.
Interventions: intervention 1: Levothyroxine intervention 2: Liothyronine intervention 3: Placebo
Intervention descriptions: intervention 1: levothyroxine sodium tablet for oral use intervention 2: Liothyronine sodium tablets for oral use treatment of hypothyroidism intervention 3: inert sugar tablets for oral use blinding for treatment of hypothyroidism

Protocol documents:
Prot_SAP_001.pdf: 
1 
 
Title: Energy Metabolism in Thyroidectomized Patients   
Protocol #:  HM20016169 
 
Principal Investigator: 
Angeliki Stamatouli, M.D. 
Division of Endocrinology Diabetes and 
Metabolism 
Department of Internal Medicine 
1101 East Marshall Street, 7th floor 
Richmond, Virginia 23298 
(804) 828-9696 
Angeliki.Stamatouli@vcuhealth.org 
 
Sub-investigator/Responsible Investigator:  
Antonio Abbate, MD, PhD 
Shanshan Chen, PhD 
Le Kang, PhD 
Giao Q. Phan, MD 
Jeremy Turlington 
Roshanak Markley 
Ritu Madan, MD 
 
 
 
 
Biostatistician: 
Shanshan Chen, PhD 
Le Kang, PhD 
 
 
Genotyping: 
Bin Ni, PhD 
 
 
Responsible Research Nurse: 
Joyce R. Ruddley RN, BSN, CCRP 
 
 
Funding Sponsor:   
NIH National Institute of Health  
 
 
Investigational Agent(s):  
 
Levothyroxine 
Liothyronine  
Placebo 
Document Version: 
Final 5.0 
 Document Version Date: 
02/02/2023 


2 
 
PROTOCOL SUMMARY 
 
Title: 
Energy Metabolism in Thyroidectomized Patients   
Protocol Number: 
 HM20016169 
IND Sponsor: 
Not applicable. 
Principal 
Investigator /Study 
Chair/Coordinating 
Center/Sponsor-
Investigator: 
Angeliki Stamatouli, M.D.  
Study Sites: 
Virginia Commonwealth University 
Division of Endocrinology Diabetes and Metabolism 
Department of Internal Medicine 
1101 East Marshall Street 
Sanger Hall, 7th floor  
Richmond, Virginia 23298 
 
Virginia Commonwealth University Health System 
Clinical Research Services Unit 
North Hospital 8th floor 
1300 East Marshall Street 
Richmond, Virginia 23219 
 
 
Clinical Trial Phase: Pilot Study 
Study Disease: 
Surgical hypothyroidism, Weight gain, Energy Expenditure  
Main  
Eligibility Criteria: 
 
Age ≥18-89 years of age  
Clinical indication for total thyroidectomy TSH at screening >0.45 <4.5 
mIU/ml 
Total Thyroidectomy for benign goiter or thyroid cancer not requiring 
suppressive thyroid hormone therapy 
Ability to understand and the willingness to sign a written informed 
consent document. 
 
Primary Objectives:  
To characterize changes in energy metabolism following 
thyroidectomy in response to LT3/LT4 vs. LT4 therapy. 


3 
 
We will perform dense phenotyping including energy expenditure and 
substrate utilization during a up to 24-hour stay in a whole-room indirect 
calorimeter before, and at three and six months following the surgery. 
These data will enable us to define in detail the changes in weight and 
energy metabolism due to the lack of endogenous thyroid hormone 
production, and the response to LT3/LT4 therapy. 
 
Secondary 
Objectives: 
To determine the effects of thyroidectomy and response to 
therapy on cardiovascular and endothelial function.  
This aim will provide novel information on the effects of hypothyroidism 
on cardiovascular function, in a well-defined experimental model, and 
of the potential for LT3/LT4 therapy in preventing hypothyroidism-
associated myocardial dysfunction and excess of cardiovascular risk. 
 
Tertiary Objectives 
To characterize the changes in lipid metabolism following 
thyroidectomy. In this aim, we will be able to define the changes in 
serum lipids as a consequence of post-surgical hypothyroidism, and to 
estimate whether LT3/LT4 is superior to LT4 therapy with respect of 
this important endpoint associated with cardiovascular risk. 
 
Endpoints: 
Primary. Differences in weight between LT4 alone or LT3/LT4  
therapy. 
Primary. Differences in Energy Expenditure between LT4 alone or 
LT3/LT4 therapy.  
Secondary. Differences in echocardiogram parameters between LT4 
alone or LT3/LT4 therapy. 
Secondary. Differences in Lipid levels between LT4 alone or LT3/LT4 
therapy. 
Exploratory. Effects of the Thr92Ala D2 variant on the primary and 
secondary endpoints. 
Exploratory. Differences in QoL (ThyPRO-39) between LT4 alone or 
LT3/LT4 therapy. 
 
Study Design: 
This is a pilot, randomized, double-blind, controlled, parallel study 
in which thirty patients will be phenotypically characterized at baseline 
before surgery, 3 and 6 months following surgery.  There will be one 6 
week post-surgery dose adjustment visit. Both groups will receive 
active therapy for the treatment of hypothyroidism: either LT4 and 
placebo or LT4/LT3 combination therapy. 
 
 
Study 
Agent/
Intervention 
Description: 
Levothyroxine and placebo or Levothyroxine/Liothyronine 
combination. 
 


4 
 
Number 
of 
Subjects: 
30 
Subject 
Participation 
Duration: 
6 Months 
Estimated Time to 
Complete 
Enrollment: 
1 year 
Statistical 
Methodology: 
Our preliminary estimate is based on the findings of our cross-over 
study with a population of 14 patients (13 female, weight (kg) = 
69.7±12.5, age (years) =49.3±8.0. After substitution of LT3 for LT4 a 
decrease in weight was 1.8±1.9 kg, and in LDL-cholesterol was 13%. 
In this study LT3 treatment resulted in 85% higher morning serum T3 
level as compared to LT4. From our recent study, the estimated 
increase in serum T3 level on LT3/LT4 combination therapy adopted in 
the current proposal would be about 44% as compared to LT4 alone, 
approximately half of the increase in serum T3 observed with full LT3 
substitution. Using the point estimates of our recent meta-analysis, the 
predicted weight gain occurring after thyroidectomy is 1.4 to 2.2 Kg. 
Similarly, no study has measured changes in energy expenditure using 
WRIC in similar study populations, and our crossover intervention did 
not show significant differences in REE between LT3 only and LT4 
treatments despite a significant change in body weight. 
We hypothesize that LT3/LT4 therapy will be superior to LT4, likely to 
a smaller effect than LT3 alone. We do not expect that the effect would 
be larger than that of pure LT3 therapy. On the other hand, the complex 
interaction of LT4 and LT3 means that an optimal combination ratio may 
exist theoretically that outperforms the pure LT3 therapy. Based on our 
empirical observations and extrapolations, we enumerate a few 
possible effect size to estimate the required sample sizes in a two-arm, 
randomized, cross-sectional design, given a significance level of 0.05. 
The following sample size calculation and statistical power estimation 
are obtained based on two-sample, one-sided t-test based on weight 
loss in LT3/LT4 as compared to LT4 alone. 
 
Weight 
Loss 
LT3/LT4 
SD 
(kg)
Power 
(%) 
Sample 
Size 
per 
Weight 
Loss 
LT3/LT4 
SD 
(kg) 
Power 
(%) 
Sample 
Size 
per 
1.4 
1.9 62.7 
15 
1.4 
1.9 80.8 
24 
1.6 
1.9 72.7 
15 
1.6 
1.9 81.6 
19 
1.8 
1.9 81.2 
15 
1.8 
1.9 81.2 
15 
2.0 
1.9 87.8 
15 
2.0 
1.9 80.3 
12 
2.2 
1.9 92.6 
15 
2.2 
1.9 80.1 
10 
1.4 
2.3 49.3 
15 
1.4 
2.3 80.9 
35 
1.6 
2.3 58.5 
15 
1.6 
2.3 81.0 
27 
1.8 
2.3 67.2 
15 
1.8 
2.3 80.2 
21 
2.0 
2.3 75.1 
15 
2.0 
2.3 81.9 
18 
2.2 
2.3 81.9 
15 
2.2 
2.3 81.9 
15 


5 
 
Power and sample size calculation for weight differences 
following thyroidectomy between LT4 and LT4/LT3 combination 
therapy. The left columns indicate the power of the study on the 
current sample size (dictated by the time and funding constrains 
of the R21 funding mechanism). The right columns indicate the 
sample size calculations necessary to assure an 80% power with 
a significance of 0.05. 
Similarly, power and sample size calculations for changes in lipids were 
based on our original cross-over study which was associated with 13% 
reduction in LDL and 12% reduction in non-HDL. From our preliminary 
study, the estimated increase in serum T3 level on LT3/LT4 
combination therapy would be about 44% as compared to LT4 alone. 
With linear extrapolation, a 5% to 8% reduction in LDL or non-HDL for 
this study is hypothesized. We also provide the sample size calculation 
and power estimation for the hypothesized percent reduction in 
LDL/non-HDL given the LDL of 122.6±25.2 (mg/dl) for LT4 group. 
 
 
% reduction 
in LDL 
LT3/LT4 vs LT4 
SD 
(%) 
Power 
(%) 
Sample 
Size per 
Arm 
% reduction 
in LDL 
LT3/LT4 vs LT4 
SD 
(%) 
Power 
(%) 
Sample 
Size per 
Arm 
5% 
10 49.7 
15 
5% 
10 
80.4 
34 
6% 
10 62.6 
15 
6% 
10 
80.7 
24 
7% 
10 74.2 
15 
7% 
10 
81.0 
18 
8% 
10 83.5 
15 
8% 
10 
81.1 
14 
5% 
12 39.9 
15 
5% 
12 
80.7 
49 
6% 
12 49.7 
15 
6% 
12 
80.4 
34 
7% 
12 60.5 
15 
7% 
12 
80.2 
25 
8% 
12 70.5 
15 
8% 
12 
81.4 
20 
 
Power and sample size calculation for differences in LDL-
cholesterol following thyroidectomy between LT4 and LT4/LT3 
combination therapy. The left columns indicate the power of the 
study on the current sample size (dictated by the time and funding 
constrains of the R21 funding mechanism). The right columns 
indicate the sample size calculations necessary to assure an 80% 
power with a significance of 0.05. 
Given the sample size of 15, we further estimate the statistical power 
of detecting differences in energy expenditure. Based on our recent 
pilot study on assessing resting metabolic rate (RMR) across 12 
healthy, normal weight subjects (including both sexes, BMI: 24.1 ± 2.9, 
age: 25~71), we estimated that the within-subject variation in RMR is 
less than 0.15 kcal/min, whereas our instrument variation is less than 
0.05 kcal/min within a day. Therefore, using the same cross-sectional 
design of 15 patients per arm, assuming we can detect a difference in 
RMR of 0.14 kcal/min (which is more than two times of the instrument 
precision), we can achieve a sufficient power of 80% with a significance 
level of 0.05 using a one-sided two-sample t-test. 
For the exploratory aims, we plan to assess if the response to ThyPRO-
39, a QoL questionnaire/instrument would yield significant difference 
between subjects on LT4/LT3 vs LT4 alone. We are also interested in 


6 
 
assessing potential genetic heterogeneity underlying the treatment 
group effect. More specifically, we would model the QoL endpoints 
using the ANOVA models incorporating treatment effect (LT4/LT3 vs 
LT4 alone), Thr92Ala D2 polymorphism (Thr/Thr, Thr/Ala, vs Ala/Ala), 
and their interaction effects. This would depict a better picture of which 
genetic group might benefit the most from LT4/LT3 combo therapy. This 
ANOVA modeling strategy can be extended in a straightforward 
manner to ANCOVA to assessing changes in other outcomes of 
interest, adjusting for potential genetic heterogeneity, as well as serum 
T3 level, and other important covariates.  
Notice that even if the primary endpoints are expressed as differences 
between baseline and end of the study, in the LT3/LT4 vs LT4 alone 
groups, we are collecting phenotypic data at each follow-up time point. 
This will offer great opportunities to characterize the longitudinal 
profiles of these phenotypic data and to estimate the effect size as well 
as the standard deviation over time, essentially the trajectory of these 
measured endpoints over the 6-month time period. Ultimately, this 
would help size a much more powerful study that analyzes the repeated 
measures of the phenotypic data, or design a sufficiently powered study 
with a limited number of subjects due to the elimination of inter-subject 
variation. For example, with 4 time points planned for the study, even if 
the power to assess the treatment effect difference on the weight loss 
of 1.4 (SD=1.9) is 62.7% given a sample size of 15 vs 15 (LT4/LT3 vs 
LT4 alone), the power to detect the treatment by time effect could range 
from 80% up to 95% depending on mean trajectory change, and the 
correlation structures between measurements at different time points 
from a repeated measures ANOVA/ANCOVA modeling. We believe 
this is a significant strength in our dense phenotyping approach with 
multiple time points, particularly in consideration of the exploratory 
scope of the R21 funding mechanism. 


7 
 
SCHEMA 
Table 1: Schedule of Events. 
 
• * Analyses run in the Department of Endocrine Lab 
• ** +/- 7 days 
• a  Analyses run in the VCU Health Department of Pathology  
• b  Visit in Whole Room Indirect Calorimeter may be up to 24 hours 
  
 
 
 
 
 
 
 
 
 
Procedures 
Screening Baseline 6  Weeks** 3 Months** 
 6  Months** 
Informed Consent 
X 
 
 
 
 
Confirm 
Inclusion/Exclusion 
X 
 
 
 
 
Medical History  
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
Weight 
X 
 
 
 
 
Vital Signs 
X 
 
 
 
 
TSH a 
X 
X 
X 
X 
X 
HbA1c a or Fructosamine 
X 
 
 
 
 
TPO Antibodiesa 
X 
 
 
 
 
24 Hour Resting Energy 
Expenditure  
(Whole Room Indirect 
Calorimeter) b 
 
X 
 
X 
X 
Genomic DNA* 
 
X 
 
 
 
Free T4* 
 
X 
 
X 
X 
Free T3* 
 
X 
 
X 
X 
Lipids*a 
 
X 
 
X 
X 
Serum Storage* 
 
X 
X 
X 
X 
Echocardiogram 
 
X 
 
X 
X 
ThyPro-39 
Quality of Life 
Questionnaire  
 
X 
 
X 
X 
DXA scan 
 
X 
 
 
X 
Randomization 
 
X 
 
 
 
Study drug dispensation 
 
X 
X 
X 
 
Dosing Adjustments 
 
 
X 
X 
 


8 
 
REVISION HISTORY 
Revision history is presented in reverse order so that the information pertaining to the most 
current version of the protocol is presented first in this section. 
Version Number 
Date of Issue 
Type of Revision 
Brief Description of the 
Revision  
Version 1, 
01/22/2020 
Initial Protocol submission 
 
Version 2               03/18/2020 
Revised version of the initial 
submission 
Added 10.7 added End of 
Study Directions 
Version 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11/03/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revise  version 2.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revise Exclusion criteria 2 
Current: 
Graves’ disease or thyroid 
autoimmunity defined by 
anti-thyroid 
peroxidase 
(TPO) antibodies titer > 35 
IU/mL  
Changed to: 
Graves’ disease or thyroid 
autoimmunity 
Clarify:  TPO antibodies to 
be 
analyzed 
in 
VCU 
Pathology Central Lab 
Current: 
9.12  ClearSight System 
This device consists of a 
small cuff that will be 
applied over two fingers, 
and based on the principle 
of 
plethysmography 
records blood pressure, 
cardiac output, endothelial 
function 
and 
systemic 
vascular resistance. The 
measurements 
will 
be 
performed at baseline, 3-
months, 
and 
6-months 
visits. 


9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Change to:  Deleted   
Deleted 
ClearSight 
procedures 
for 
Study 
visits Baseline, 3 month 
and 6 month will not be 
done 
 
Current:  
Study visits Baseline, 3 
month and 6 month 
 
 You will be fitted with five 
accelerometers (one on 
each limb plus chest) to 
record 
spontaneous 
movements 
 
Changed to : 
Study visits Baseline, 3 
month and 6 month 
 
You will be fitted with five 
accelerometers (one on 
each limb plus chest) to 
record 
spontaneous 
movements 
 (maybe done based upon 
availability) 
 
Study visits Baseline, 3 
month and 6 month 
 
Accelerometers Fitting - 
subject will be fitted with 
five (one on each limb plus 
chest) 
to 
record 
spontaneous movements.  
 
Changed to:  
Study visits Baseline, 3 
month and 6 month 
 
Accelerometers Fitting - 
subject will be fitted with 


10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
five (one on each limb plus 
chest) 
to 
record 
spontaneous movements 
(maybe done depending 
upon availability)  
 
Current: 
Study visits Baseline, 3 
month and 6 month 
 
Each 
of 
the 
three 
phenotyping 
visits 
will 
include 
a 
24-hour 
recording 
of 
energy 
expenditure in the whole 
room calorimeter. 
 
 
Change to: 
Study visits Baseline, 3 
month and 6 month 
 
Each 
of 
the 
three 
phenotyping 
visits 
will 
include an up to 24-hour 
recording 
of 
energy 
expenditure in the whole 
room calorimeter. 
Current: 
Study visits Baseline, 3 
month and 6 month 
Standardized Meals will be 
served at 13:00, and at 
18:00, each representing 
1/3 of the estimated EE 
with 
the 
following 
macronutrient 
composition: 
50% 
carbohydrate, 
20% 
protein, 
30% 
fat. 
Approximate total energy 
needs 
for 
weight 
maintenance 
will 
be 


11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
calculated 
using 
the 
Mifflin-St. Jeor equation 
(89). EE recording will be 
completed at 11:00 of the 
following day,  
 
Changed:  
Study visits Baseline, 3 
month and 6 month 
Standardized Meals will be 
served at 13:00 (if already 
entered in the WRIC), and 
at 
18:00, 
each 
representing 1/3 of the 
estimated EE with the 
following 
macronutrient 
composition: 
50% 
carbohydrate, 
20% 
protein, 
30% 
fat. 
Approximate total energy 
needs 
for 
weight 
maintenance 
will 
be 
calculated 
using 
the 
Mifflin-St. Jeor equation 
(89). EE recording will be 
completed 
at 
approximately 11:00 of the 
following day,  
 
Current:   
Study visits Baseline, 3 
month and 6 month 
EE 
recording 
will 
be 
completed 
at 
approximately 11:00 of the 
following day, 
 
 
Change 
Study visits Baseline, 3 
month and 6 month 


12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EE 
recording 
will 
be 
completed at 11:00 of the 
following day, 
Current: 
Volunteers will enter the 
WRIC at 11:00 and will 
receive 
standardized 
meals at 13:00  
Change: 
Volunteers will enter the 
WRIC 
at 
the 
earliest 
at11:00 and will receive 
standardized 
meals 
at 
13:00 (if already entered in 
the WRIC), 
Current: 
Exclusion 
Criteria 
Uncontrolled 
diabetes 
(HbA1c 
> 
8% 
at 
screening) 
Change: 
Exclusion 
Criteria 
Uncontrolled 
diabetes 
(HbA1c 
> 
8% 
or 
fructosamine 
< 
325 
mcmol/l in substitution of 
HbA1c to reflect recent 
improvement in diabetes 
control at screening 
Current: 
Exclusion 
Criteria 
Weight <50 or >100 Kg; 
Change: 
Exclusion 
Criteria 
Weight <50 or >150 Kg; 
 


13 
 
 
Version 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 5.0 
 
03/13/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2/2/2023 
 
Revision to Version 3 to 
include provisions to 
address drug-drug 
interactions 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revision to address change in 
Principle Investigator  
 
 
 
 
 
 
 
 
 
 
 
Changed the name of the 
Laboratory where samples are 
separated, aliquot and stored 
to Department of Endocrine 
Laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Advice to contact study 
team in case of new 
medications, 
or 
dose 
changes 
in 
current 
medications. 
Reduction  to 1.2 mcg/Kg 
(-25 mcg in case of 
randomization 
to 
the 
levothyroxine/liothyronine 
group) of initial study drug 
dose in patients taking oral 
semaglutide 
 
Current 
Principle 
investigator: 
Francesco Celi, MD MHSc 
ChangeDeleted 
Francesco 
Celi, 
MD, 
MHSc. as PI and changed 
the Principle investigator 
to  to Angeliki Stamatouli, 
MD 
Current Serum will be 
separated 
by 
centrifugation, aliquot in 1 
mL cryoviales and stored 
in -80⁰C freezers In Dr. 
Celi’s Lab in Sanger Hall  
changed to  
Change 
Serum will be separated 
by centrifugation, aliquot in 
1 mL cryoviales and stored 
in -80⁰C freezers In the 
Department of Endocrine 
Lab in Sanger Hall 
 


14 
 
 
Added a Sub investigator  
 
 
 
Add an unblinded physician 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Added a Sub investigator 
Ritu Madan. MD  
Current  
Dose adjustments will be 
performed at the 6-week 
and 3-month follow up 
visits by an unblinded 
endocrinologist 
(Dr. 
Yavuz) aiming to achieve 
and maintain a target TSH 
within the normal range 
and within ± 0.5 mcIU/ml 
from the baseline (pre-
surgery) TSH, according 
to the scheme in Table 1.  
Change  
Dose adjustments will be 
performed at the 6-week 
and 3-month follow up 
visits by an unblinded 
endocrinologist 
(Dr. 
Madan) aiming to achieve 
and maintain a target TSH 
within the normal range 
and within ± 0.5 mcIU/ml 
from the baseline (pre-
surgery) TSH, according 
to the scheme in Table 1. 
Doses will be rounded to 
the 
nearest 
available 
formulation 
Current  
a physician who is board-
certified in Endocrinology 
and 
Internal 
Medicine. 
Additionally, the unblinded 
physician (Yavuz) 
Change  
a physician who is board-
certified in Endocrinology 
and 
Internal 
Medicine. 


15 
 
 
 
 
 
Analysis of  Lipids samples 
Additionally, the unblinded 
physician (Madan) 
Current 
 
Analyses run in Dr Celi’s 
Lab   
 
Change 
 
Analysis run in   VCU 
Health 
 
Department  
Pathology  Laboratory  
 


16 
 
TABLE OF CONTENTS 
 
 
PROTOCOL SUMMARY ................................................................................................................ 2 
SCHEMA ......................................................................................................................................... 7 
REVISION HISTORY ...................................................................................................................... 8 
TABLE OF CONTENTS ............................................................................................................... 16 
LIST OF ABBREVIATIONS ......................................................................................................... 20 
1 
BACKGROUND ............................................................................................................. 22 
2 
RATIONALE .................................................................................................................. 24 
3 
TRIAL OBJECTIVES..................................................................................................... 25 
3.1 
AIM 1:  TO CHARACTERIZE CHANGES IN ENERGY METABOLISM FOLLOWING THYROIDECTOMY 
IN RESPONSE TO LT3/LT4 VS. LT4 THERAPY.................................................................... 25 
3.2 
AIM 2: TO DETERMINE THE EFFECTS OF THYROIDECTOMY AND RESPONSE TO THERAPY ON 
CARDIOVASCULAR AND ENDOTHELIAL FUNCTION............................................................... 26 
3.3 
AIM 3: TO CHARACTERIZE THE CHANGES IN LIPID METABOLISM FOLLOWING 
THYROIDECTOMY. ............................................................................................................ 27 
3.4 
EXPLORATORY AIMS: TO EVALUATE THE CHANGES IN THYPRO-39, A THYROID SPECIFIC 
QUALITY OF LIFE INSTRUMENT, AND THE ROLE OF THE THR92ALA D2 POLYMORPHISM IN 
POST-SURGICAL THYROIDECTOMY PATIENTS TREATED WITH LT4 OR LT3/LT4 COMBINATION 
THERAPY. ........................................................................................................................ 28 
4 
STUDY DESIGN ............................................................................................................ 29 
5 
PATIENT SELECTION .................................................................................................. 29 
5.1 
INCLUSION CRITERIA ........................................................................................................ 29 
5.1.1 
Clinical indication for total thyroidectomy TSH at screening> 0.45<4.5 mIU/m ................................ 29 
5.1.2 
Euthyroid patients with clinical indication for total thyroidectomy ...................................................... 29 
5.1.3 
Indication to total thyroidectomy for benign goiter or thyroid cancer not requiring                 
suppressive thyroid hormone therapy ................................................................................................................. 29 
5.1.4 
Age 18-89 years of age  .......................................................................................................................... 29 
5.1.5 
Males and females .................................................................................................................................. 29 
5.2 
EXCLUSION CRITERIA ....................................................................................................... 30 
5.2.1 
Weight <50 or >150 Kg; ....................................................................................................................... 30 
5.2.2 
Graves’ disease 35  ................................................................................................................................ 30 
5.2.3 
Use of thyroid hormone therapy use of thyroid hormone therapy or thyroid   supplements (at 
screening) except for multinodular goiter; ......................................................................................................... 30 
5.2.4 
Indication for thyroid hormone suppressive therapy following surgery ................................................ 30 
5.2.5 
Uncontrolled arterial hypertension. (Stage 2 or greater on medication); (>140/90 mmHg at screening 
while on medication (patients with hypertension controlled by therapy will be allowed to participate). .......... 30 
5.2.6 
Cardiovascular disease: congestive heart failure; unstable coronary artery disease (angina, coronary 
event, or revascularization within 6 months); atrial fibrillation, arrhythmia or ventricular arrhythmia, ......... 30 
5.2.7 
Pregnancy, breastfeeding, or planned pregnancy within six months from the   thyroidectomy ............ 30 
5.2.8 
History of major depression or psychosis;............................................................................................. 30 
5.2.9 
Uncontrolled diabetes (HbA1c > 8% or fructosamine < 325 mcmol/l in substitution of HbA1c to 
reflect recent improvement in diabetes control at screening) ............................................................................. 30 
5.2.10 Conditions that in the opinion of the PI may impede the successful completion of       the study ......... 30 
6 
STUDY ENTRY AND WITHDRAWAL PROCEDURES ............................................... 30 


17 
 
6.1 
STUDY ENTRY PROCEDURES ........................................................................................... 30 
6.1.1 
Required Pre-Registration Screening Tests and Procedures................................................................. 30 
6.2 
STUDY WITHDRAWAL PROCEDURES ................................................................................. 31 
6.2.1 
A patient is free to withdraw from the study for any reason, at any time, without reason for doing so 
and without any penalty of prejudice. ................................................................................................................. 31 
6.2.2 
A patient may be removed from treatment for one of the following criteria: ........................................ 31 
6.2.3 
The study physician thinks it is necessary for the health and safety of the patient. ............................... 31 
6.2.4 
Principal Investigator’s decision to discontinue the study. ................................................................... 31 
6.2.5 
The patient is non-compliant with the protocol ..................................................................................... 31 
6.2.6 
If an adverse event (including worsening of the concomitant illness) develops which is considered by 
the Investigator as incompatible with continuation of the study ......................................................................... 31 
6.2.7 
Administrative reasons that require the patient to withdrawal ............................................................. 31 
6.2.8 
If pregnancy develops ............................................................................................................................ 31 
6.2.9 
Lost to follow-up .................................................................................................................................... 31 
6.2.10 Patient death .......................................................................................................................................... 31 
6.2.11 All available data will be collected if feasible.  The reason for discontinuation should be documented 
in the case report form (CRF). ............................................................................................................................ 31 
7 
PREMATURE TERMINATION ...................................................................................... 32 
8 
TREATMENTS .............................................................................................................. 32 
8.1 
INVESTIGATIONAL /NON INVESTIGATIONAL PRODUCTS ...................................................... 32 
8.2 
STUDY DOSING GROUP .................................................................................................... 33 
8.3 
DOSAGE AND ADMINISTRATION ......................................................................................... 33 
9 
STUDY PROCEDURES ................................................................................................ 34 
STUDY VISIT PROCEDURES ..................................................................................................... 34 
9.1 
INFORMED CONSENT ........................................................................................................ 35 
9.2 
MEDICAL HISTORY: .......................................................................................................... 35 
9.3 
PHYSICAL EXAMINATION ................................................................................................... 35 
9.4 
ENERGY EXPENDITURE RECORDINGS .............................................................................. 35 
9.5 
ANTHROPOMETRIC DATA .................................................................................................. 36 
9.6 
BLOOD COLLECTION ........................................................................................................ 36 
9.7 
ACCELEROMETERS .......................................................................................................... 36 
9.8 
GENETIC MATERIAL .......................................................................................................... 36 
9.9 
QUALITY OF LIFE ASSESSMENT ......................................................................................... 37 
9.10 
DXA SCAN (DUAL-ENERGY X-RAY ABSORPTIOMETRY):..................................................... 37 
9.11 
ECHOCARDIOGRAM (ECHO) .............................................................................................. 37 
10 
STUDY VISITS .............................................................................................................. 37 
10.1 
OVERALL STUDY SCHEDULE ............................................................................................. 37 
10.2 
SCREENING/INCLUSION .................................................................................................... 37 
(SCREENING VISIT) ..................................................................................................................... 37 
O 
THYROID PEROXIDASE ANTIBODY (TPO ANTIBODIES) ....................................................... 38 
O 
THYROID STIMULATING HORMONE (TSH) ......................................................................... 38 
O 
HGA1C (FOR SUBJECTS WITH A HISTORY OF DIABETES) .................................................... 38 
THE ENDOCRINOLOGIST WILL DETERMINE STUDY ELIGIBILITY. ELIGIBLE SUBJECTS WILL PROCEED 
TO THREE IDENTICAL OVERNIGHT PHENOTYPING VISITS AND ONE OUTPATIENT DOSE 
ADJUSTMENT VISIT:......................................................................................................... 38 
O 
(VISIT 1)  BASELINE .......................................................................................................... 38 
O 
(VISIT 2)  THREE MONTH AFTER SURGERY  AND ................................................................ 39 
O 
6 WEEK DOSE ADJUSTMENT VISIT ................................................................................... 39 


18 
 
O 
(VISIT 3)  SIX MONTH VISIT  END OF STUDY ....................................................................... 39 
10.3 
PHENOTYPE VISIT 1 (BASELINE) ....................................................................................... 39 
10.3.1 Two (2) days prior to the Phenotype Visit 1 Baseline .......................................................................... 39 
SUBJECTS WILL BE INSTRUCTED TO: ............................................................................................ 39 
O 
REFRAIN FROM STRENUOUS EXERCISE ............................................................................. 39 
O 
REMAIN ON A REGULAR DIET............................................................................................. 39 
10.3.2 Twenty four (24) hours prior to Surgery Phenotype Visit 1 Baseline ................................................. 39 
SUBJECTS WILL BE ADMITTED TO THE HOSPITAL ON THE CLINICAL RESEARCH SERVICES UNIT FOR 
AN INPATIENT STAY IN THE WHOLE ROOM INDIRECT CALORIMETER (WRIC) PRIOR TO SURGERY ......... 39 
10.4 
SIX WEEK POST SURGERY ............................................................................................... 40 
10.5 
PHENOTYPE VISIT 2 (MONTH 3)........................................................................................ 40 
10.6 
PHENOTYPE VISIT 3 (MONTH 6)........................................................................................ 41 
    10.7    End of study Treatment……………………………………………………………………33 
11 
STUDY RECRUITMENT AND RETENTION ................................................................ 42 
11.1 
RECRUITMENT.................................................................................................................. 42 
11.1.1 Recruitment of Women, children and minority individuals study ...................................................... 42 
11.1.2 Recruitment and retention plan ............................................................................................................ 42 
11.2 
RETENTION ...................................................................................................................... 42 
12 
DATA AND SAFETY MONITORING PLAN (DSMP) ................................................... 43 
13 
CLINICALTRIALS.GOV REQUIREMENTS: ................................................................ 43 
14 
ADVERSE EVENTS ...................................................................................................... 44 
15 
ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS .............. 45 
15.1 
DEFINITIONS .................................................................................................................... 45 
15.1.1 Adverse Event (AE) ................................................................................................................................ 45 
15.1.2 Serious AE (SAE) ................................................................................................................................... 45 
15.1.3 Unanticipated Problem (UP) ................................................................................................................. 45 
15.1.4 AE Description and Grade ..................................................................................................................... 46 
15.1.5 AE Expectedness .................................................................................................................................... 46 
15.1.6 AE Attribution ........................................................................................................................................ 46 
15.2 
KNOWN AES LIST ............................................................................................................. 46 
15.3 
TIME PERIOD AND GRADE OF AE CAPTURE ...................................................................... 47 
15.4 
PROCEDURES FOR RECORDING AES, SAES, AND UPS ..................................................... 50 
15.5 
ROUTINE REPORTING PROCEDURES FOR AES ................................................................. 51 
15.6 
EXPEDITED REPORTING PROCEDURES FOR SAES, UPS, AND DLTS ................................. 51 
15.7 
RESOURCE SHARING PLAN ............................................................................................... 52 
16 
REGULATORY COMPLIANCE AND ETHICS ............................................................. 53 
16.1 
ETHICAL STANDARD ......................................................................................................... 53 
16.2 
REGULATORY COMPLIANCE.............................................................................................. 53 
16.3 
INSTITUTIONAL REVIEW BOARD ........................................................................................ 53 
16.4 
INFORMED CONSENT PROCESS ........................................................................................ 53 
16.5 
SUBJECT CONFIDENTIALITY AND ACCESS TO SOURCE DOCUMENTS/DATA ........................ 54 
17 
DATA HANDLING AND RECORD KEEPING .............................................................. 55 
17.1 
DATA MANAGEMENT RESPONSIBILITIES ............................................................................ 55 
17.2 
SOURCE DOCUMENTS ...................................................................................................... 55 
17.3 
CASE REPORT FORMS ..................................................................................................... 55 
17.4 
STUDY RECORD RETENTION ............................................................................................ 55 


19 
 
18 
REFERENCES .............................................................................................................. 56 
 
19 
    APPENDICES …………..…………………………………………..………………………55 


20 
 
LIST OF ABBREVIATIONS 
Abbreviations 
Description of abbreviations 
AE 
Adverse Event 
AM 
Morning 
BIA 
Bio-electrical Impedance Analysis 
BMI 
Body Mass Index 
BMR 
Basal Metabolic Rate 
°C 
Celsius 
Cmax 
Maximum Plasma Concentration 
CRF 
Case Report Form 
CRSU 
Clinical Research Service Unit 
CT 
Computerized Tomography 
DNA 
Deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
DSMP 
Data and Safety Monitoring Plan 
Echo 
Echocardiogram 
EE 
Energy Expenditure 
ENT 
Ears, Nose, and Throat 
° F 
Fahrenheit 
FOA 
Funding Opportunity Announcement (NIH) 
GWAS 
Genome-wide association study 
HgA1c 
Glycated Hemoglobin 
IU 
International Units 
IRB 
Institutional Review Board 
Kg 
Kilogram 
kca 
kilocalories 


21 
 
LT3 
Liothyronine 
LT4 
Levothyroxine 
mcg  
micrograms 
ml 
milliliter 
Na-EDTA 
Ethylenediamine Tetraacetic Acid 
NIH 
National Institutes of Health 
PET 
Positron Emission Tomography 
PHI  
Protected Health Information 
PK 
Pharmacokinetics 
PM 
Night 
QOL 
 
Quality of Life 
SAE 
Serious Adverse Event 
Tmax 
Time to achieve Cmax 
TSH 
Thyroid-stimulating hormone 
TPO 
Thyroid peroxidase 
T3 
triiodothyronine  
Free T4 
Thyroxine 
UP 
Unanticipated Problem 
VCU 
Virginia Commonwealth University  
Wi-Fi 
Wireless Networking Technology 
WRIC 
whole room indirect calorimeter 


22 
 
1 BACKGROUND 
Hypothyroidism is a common condition, particularly among women (1, 2). Weight gain despite 
optimal levothyroxine (LT4) replacement therapy is a common and distressful occurrence in 
hypothyroidism (3), leading to frequent modifications in therapy (4) with negligible 
improvements and to patients’ dissatisfaction. Importantly, weight gain has been consistently 
recognized as a driver of poor quality of life in hypothyroid patients (3, 5-8). Additionally 
hypothyroidism is associated with dyslipidemia (9-11) and myocardium dysfunction and 
increased cardiovascular risk (12-16). There is a need to characterize in detail the changes in 
energy metabolism in hypothyroidism, and to study the effects of alternative treatment 
modalities directed to minimize the prevalence and severity of hypothyroid symptoms. Previous 
studies directed to assess the efficacy of combination liothyronine (LT3)/LT4 therapies aimed 
to supplement for the loss of endogenous T3 were underpowered, with heterogeneous study 
populations, and often with inadequate treatment scheme (17-29). Virtually all the professional 
organizations lament the lack of high quality, definitive data to support or deny the use of 
combination therapy for the treatment of hypothyroidism (30-32). Post-surgical hypothyroidism 
represents an ideal model to study the effects of loss of endogenous production of thyroid 
hormone and of therapeutic modalities because of the absence of confounders due to residual 
endogenous hormone production and long transition from eu- to hypothyroidism. By combining 
the study population characteristics with our ability to perform dense phenotyping, and a 
rigorous study design, we will conduct a proof-of-concept study to characterize the changes in 
energy metabolism, cardiovascular function, and lipid metabolism before and after 
thyroidectomy in response to LT4 or LT3/LT4 combination therapy. The results of this study, 
within the scope of the R21 funding mechanism will define the point estimates of our 
intervention. This in turn will enable us to: a) define whether a larger study is scientifically 
warranted, b) provide for the effect size for post-thyroidectomy weight gain to adequately 
power a large trial which definitely will address the role of combination therapy for the 
treatment of hypothyroidism, and c) define effect size for secondary and exploratory aims to be 
applied to a large clinical trial.  
Irrespective of the etiology, the treatment of hypothyroidism is based on the replacement of the 
lack of endogenous production of thyroid hormone. This is commonly accomplished with LT4, 
which is metabolized by the deiodinase enzymes into T3 that ultimately delivers the hormonal 
signal to the tissues (30). This strategy is based on the assumption that the action of the 
deiodinase enzymes is able to deliver adequate T3 to all the tissue targets of thyroid hormone. 
Experimental and in vivo observations have challenged this axiom. The landmark experiments 
of Morreale d’Escobar in a rodent model of hypothyroidism demonstrated that LT4 alone is not 
sufficient to restore hypothyroidism in all tissues (33), and only administration of a combination 
of LT3  and LT4 could provide adequate restoration of T3 (34). On the clinical side, a 
significant number of patients, estimated in up to 40%, complain of residual symptoms 
attributed to hypothyroidism despite achieving the therapeutic goal of normalization of the 
Thyroid Stimulating Hormone (TSH) (3). Common symptoms include weight gain, cold 
intolerance, sluggishness, and “mental fog” (35). The persistence of hypothyroid symptoms 
has been attributed to an insufficient delivery of T3 to the target tissues because of the loss of 


23 
 
the T3 produced by the thyroid (estimated to be 20-30 mcg/day) (36) or to a deficit in 
peripheral conversion of T4 into T3, possibly due to a common polymorphism of the type 2 
deiodinase gene (37). Importantly, weight gain is considered the major driver of patients’ 
dissatisfaction (3, 5-8). The use of LT3/LT4 combination therapy was proposed to provide a 
more “physiologic” replacement and several clinical trials have been conducted (17-29); 
however, the results are inconsistent and no clear evidence has emerged. This is likely due to 
low power, different therapeutic regimens, and to the heterogeneity of the study populations, 
which were mostly composed of individuals with hypothyroidism secondary to autoimmune 
thyroid disease, which often have residual endogenous thyroid hormone production. In a 
crossover study, the substitution of desiccated thyroid extracts (DTE) for LT4 resulted in 1.27 
Kg weight loss (38). Importantly, patients who lost weight on DTE therapy had a significant 
improvement in symptoms.  Moreover, a secondary analysis of the largest LT3/LT4 trial 
indicated that carriers of the Thr92Ala D2 were more likely to have worse quality of life at 
baseline, and more robust response to LT3/LT4 combination therapy (39). In a crossover 
intervention, we observed that the substitution of LT3 alone for LT4 resulted in significant weight 
loss and lowering of cholesterol (40). Collectively, these data support the hypothesis that 
increased serum T3 levels as result of T3-containing therapeutic regimens enables weight loss, 
reduction in cholesterol, and possibly improvement in quality of life in hypothyroid patients. 
Post-surgical hypothyroidism is unique because patients become acutely devoid of 
endogenous thyroid hormone production, transitioning from a state of euthyroidism to 
hypothyroidism entirely dependent on exogenous thyroid hormone replacement. To this end, 
this form of hypothyroidism represents an ideal experimental platform to study the effects of 
loss of endogenous thyroid hormone production and of the response to therapy. Importantly, 
recent guidelines for the treatment of thyroid cancer have significantly reduced the need for 
thyroid hormone suppressive therapy, and the majority of patients undergoing total 
thyroidectomy for differentiated thyroid cancer are treated with replacement therapy aimed to 
normalization rather than suppression of the Thyroid Stimulating Hormone (TSH) (41). 
Surprisingly, little information is available on the changes in body weight and composition 
following thyroidectomy, and no thyroid hormone replacement therapy study has selectively 
recruited patients post-thyroidectomy. The reported weight gain within a year of 
thyroidectomy ranges from none to almost 3 Kg (42-47). These differences are likely due to 
retrospective nature of the analyses, methodological shortcomings, and inclusion of patients 
with pre-existing thyroid dysfunction. 
 
 
 
 
 
 
 
 


24 
 
2  RATIONALE  
 2.1 
Levothyroxine/Liothyronine (LT4/LT3) combination therapy 
 
Contrary to a smaller longitudinal study (48), Gullo and co-workers have demonstrated that 
patients on LT4 therapy have lower T3 levels than controls (49). We have shown that 
pharmacoequivalent doses of LT3, able to achieve the same TSH as LT4 (50), result in high-
normal serum T3 levels and that LT4 alone results in serum T3 levels at the low end of the 
normal range (40). The increase in serum T3 levels (and as a consequence, its increase                                     
at the target tissue level) is a likely explanation for the beneficial metabolic effects of LT3 
monotherapy. To this end, the addition of LT3 to the LT4 therapy regimen has been proposed as 
a means to overcome the lack of endogenous thyroid hormone production of T3. The definition 
of LT3 pharmacokinetics PK) is thus a necessary preliminary step to design a therapy which can 
provide adequate amount of exogenous T3 to maintain the serum levels within the normal range 
and to minimize T3 serum level fluctuations above and below the target range.  The current data 
on the LT3 PK are not clear, with an estimated half-life ranging from 6 to 22 hours (51-53). The 
wide range is in part explained by different experimental protocols and dated hormonal assays. 
We revisited this question by assessing LT3 kinetic and terminal elimination in a group of                
patients treated with LT3 alone in preparation for nuclear medicine procedures for thyroid cancer 
(NCT01441154, PI Celi). Study patients were treated with LT3 0.6 mcg/Kg/day in three daily 
doses (average dose 18.8±4.5 mcg) (50) for four weeks before undergoing last dose PK 
analysis and terminal elimination. In this population, the kinetics of LT3 can be described by a 
two-component (fast distribution and slow elimination) model with a distribution half-life of 1.1 
hour and an elimination half-life of 28.4 hour. The Tmax was reached at 1.8±0.5 hour from the 
LT3 administration, with a Cmax of 324.0±63.3 ng/dl. Based on these observations, we have 
developed a model to assess the effects of 10 mcg LT3 substitution for 25 mcg of levothyroxine 
on serum T3 levels, sufficient to increase the serum T3 levels. While a single administration 
would result in significant fluctuations of T3 levels, a twice daily administration regimen will 
provide more stable T3 serum levels, well within the normal range throughout the day. The 
therapeutic scheme adopted in this proposal is thus based on these preliminary data.  
 
2.2 
Experimental approach 
 
This proposal is based on the premise that thyroidectomized patients on levothyroxine 
replacement therapy represent an ideal experimental model to study the pathophysiology of 
hypothyroidism due to the lack of endogenous thyroid hormone production. To this end, we 
intend to perform dense phenotyping in thirty patients with clinical indications for total 
thyroidectomy at baseline (pre- surgery), and while on LT4 or LT4/LT3 combination therapy for 
a 6-month period aimed to restore the individuals’ TSH level prior to the surgery. The 
recruitment will be primarily performed from patients undergoing evaluation in the 
multidisciplinary thyroid neoplasia clinic and through ENT at Virginia Commonwealth University, 
but the study information will be disseminated among local endocrinologists, and self-referral 
will be allowed.  
 


25 
 
2.3 
Whole-room indirect calorimeters 
 
The indirect calorimeter instruments and techniques allow for non-invasive real-time recording 
of energy expenditure and respiratory quotient by measuring oxygen consumption and carbon 
dioxide production15. In comparison with alternate forms of measuring energy expenditure (the 
historically-used metabolic carts and portable calorimeters), the whole room calorimeters 
overcome the issues of: 1) Low accuracy due to environmental interference (relative humidity, 
oxygen and carbon dioxide concentration in the testing room, presence of study personnel); 2) 
Inconvenience of using a face mask or a canopy hood which limit the duration of the 
observations and the flexibility of conducting tests which require additional sensors or 
manipulations. Conversely, whole room calorimeters, by allowing free movement of the subject 
and through controlling and monitoring environmental factors (e.g. temperature, gas 
concentration in the inflow air), overcome the limitations of the metabolic carts and portable 
calorimeters. Traditionally, room calorimeters were challenged by the long equilibration period 
and limited ability of capturing dynamic interventions with time resolution of less than 30 
minutes16. At VCU, we have recently built and validated a fast-response whole-room calorimeter 
suite, which allows a fast equilibration period (10 minutes) and recording dynamic changes 
within 10-15 minutes, favorably comparable to the metabolic cart methods. Additionally, the 
environmental temperature of our systems can be modulated between 15°C - 30°C (59°F - 
86°F) while maintaining an accurate reading. Our room calorimeters are equipped with airtight 
ports for food administration,Television set, a toilet, and Wi-Fi connectivity, which enable more 
comfortable and longer studies, as well as direct observation of acute (minutes to hours) effects 
of pharmacologic interventions on energy expenditure and substrate utilization. The flexibility of 
the VCU whole-room indirect calorimeter system allows for continuous and noninvasive 
monitoring of energy expenditure, and other parameters such as heart rate and skin 
temperature, while the volunteer is in a comfortable environment.  
3 TRIAL OBJECTIVES 
3.1 Aim 1:  To characterize changes in energy metabolism following thyroidectomy in 
response to LT3/LT4 vs. LT4 therapy. 
Historically, the measurement of energy expenditure (EE) by indirect calorimetry has been used 
as an index of thyroid function (57). While overt thyrotoxicosis and hypothyroidism are  
associated with dramatic extremes in EE, small differences sufficient to generate significant 
weight changes (40) or small variations in LT4 dose fall below the detection of the ventilated 
hood (“metabolic cart”) technique (58). Additionally, the ventilated hood method does not allow 
for prolonged recordings, negating the opportunity to reliably measure the entire spectrum of the 
EE. Interestingly, a recent report indicated that the metabolic signature of chronic calorie 
restriction is low T3 and decreased sleeping EE (59). The whole room indirect calorimeter 
(WRIC) technique enables recordings of the entire spectrum of EE components, including 
resting and sleeping EE, spontaneous movements, and thermic effect of food in a near free-
living environment (60). For our WRIC system, we have recently devised and validated a data 


26 
 
analysis algorithm to overcome the suboptimal temporal resolution issue associated with 
traditional WRICs. This method minimizes the latency between events and response in EE 
recordings and enable truly minute-by-minute real-time monitoring capability of WRIC (61). 
Additionally, the continuous recording of the respiratory quotient (RQ) during controlled fasting 
enables us to assess substrate utilization and metabolic flexibility, which correlates well with the 
risk of developing metabolic complications from obesity (62). The real-time monitoring capability 
of WRIC, coupled with precise event annotation and timestamping as well as the wearable 
sensors that collect other physiological data simultaneously, allows for analysis of each 
component of EE. For example, the thermic effect of food can be found by aggregating the 
post-prandial EE 4-hours after the meal time. Sleeping/wake onset times can be detected using 
wearable activity sensors (63) and sleeping EE can be found by aggregating EE between sleep 
time and wake onset time. While no exercise will be conducted in our study, we also plan to 
monitor minute-by-minute activity counts and assess the impact of spontaneous activities on EE 
in our analysis. The optimized temporal response of our WRIC system, and expertise in 
wearable data collection and analysis, will in turn make the VCU whole room indirect calorimeter 
system uniquely poised to record small differences in the EE and its components. For the 
purpose of this study, we will perform 24-hour recordings of EE in the VCU WRIC which has a 
precision of 0.05 Kcal/min. In preliminary experiments performed in a group of liver transplant 
patients with or without non-alcoholic fatty liver disease (NAFLD), we were able to detect a 
significant difference in RQ during controlled fast (Figure 4) indicating that NAFLD adversely 
affects metabolic flexibility in this population. These data show that the VCU WRIC system is 
uniquely positioned to detect small differences in EE components which over time can result in 
significant weight changes. In our study design, study participants will undergo a total of three 
24-hour EE recordings before, three, and six months after total thyroidectomy while on LT4 
alone or LT3/LT4 therapy. Weight will be measured by a stadiometer at the end of each EE 
recording, following 15-hour fasting, after voiding. Body composition will be measured by DXA 
scan at baseline and at the completion of the study. 
Expected results. We predict that patients undergoing total thyroidectomy treated with LT4 
alone will experience a significant weight gain over a six-month period following the procedure 
despite adequate replacement therapy. Treatment with LT3/LT4 combination therapy will 
prevent weight gain while achieving TSH levels similar to the LT4-only group. Moreover, the 
longitudinal assessment of EE will provide novel and clinically relevant information on the 
effects of surgical hypothyroidism and its treatment on EE and its components. Collectively, the 
data will enable us to define in detail the changes in weight and energy balance in its  
components, and body composition due to the lack of endogenous thyroid hormone production, 
and the response to therapies. 
 
3.2 Aim 2: To determine the effects of thyroidectomy and response to therapy on 
cardiovascular and endothelial function. 
Hypothyroidism, even in the subclinical range, is an important cardiovascular risk factor (12-16) 
which is not completely eliminated by the LT4 treatment (64, 65). Experimental data indicate 
beneficial effects of LT3 supplementation in the recovering phase of cardiac surgery (66), and 
LT3 therapy has been suggested as a potential addition to the treatment of congestive heart 
failure (67). While overt hypothyroidism is associated with systolic dysfunction and congestive 


27 
 
heart failure, the effects of subclinical hypothyroidism are subtle, mostly characterized as 
diastolic dysfunction with distinct echocardiographic changes (14). Of note, in our original study, 
the LT3-only arm had a significant decrease in isovolumetric relaxation time, and a trend toward 
an increase in left ventricle end diastolic volume, suggesting an increase in compliance and 
diastolic function (40). Aside the direct effects on the heart, thyroid hormone also plays a 
significant role in the maintenance of vascular tone and endothelium function (68-70), and 
hypothyroidism is associated with an increase in systemic vascular resistance (71). To 
comprehensively assess the effects of surgical hypothyroidism on cardiovascular function, and 
to compare the effects of LT4 vs. LT3/LT4 combination therapy, we will use echocardiography 
. This is a non-invasive device based on the volume clamp method, which continuously 
measures blood pressure by clamping the artery to a constant volume by dynamically providing 
equal pressure on either side of the arterial wall, while the volume is measured by a 
photoplethysmography built into a cuff which is fitted on a hand finger. This non-invasive device 
is very precise and accurate when compared with measurement of cardiac output using 
pulmonary artery catheter thermodilution (Swan-Ganz right heart catheterization) (72, 73). The 
echocardiogram will measure left ventricular end diastolic and end-systolic volumes, calculate 
ejection fraction, and measure indirect parameters of diastolic function.. The measurements of 
diastolic parameters will include measuring the early velocity of the mitral 
annulus in diastole at pulsed wave, tissue Doppler analysis (E’) which is an indirect measure of 
myocardial relaxation and a surrogate for the myocardial relaxation constant , and the ratio of 
the early transmitral flow velocity E to E’ (E/E’), which correlates with left ventricular filling 
pressures (75). Expected results. When compared to baseline, we expect that the LT4-treated 
group will develop subtle evidence of diastolic dysfunction, while the LT3/LT4-treated group will 
show no changes, indicating that the combination therapy is able to prevent the effect of 
hypothyroidism on the cardiovascular system. Due to the exploratory nature of the proposal we 
do not expect that the results will be conclusive, but will provide a unique opportunity of  
estimating the effects of transition from a state of euthyroidism to full reliance on replacement 
therapy, and to compare the differential response to LT4 vs. LT3/LT4 therapy on the 
cardiovascular system. The point estimates obtained from this proposal will then enable us to 
design an adequately powered study to assess the effects of thyroid hormone replacement on 
cardiovascular function. 
 
3.3 Aim 3: To characterize the changes in lipid metabolism following thyroidectomy. 
 
Thyroid hormone exerts pervasive actions on lipid metabolism by directly regulating 
transcription of the LDL receptor, intracellular metabolism of cholesterol within the hepatocyte, 
cholesterol excretion and reabsorption through the biliary tract, and peripheral lipolysis (10, 76). 
Hypothyroidism results in significant, reversible hypercholesterolemia, which in turn contributes 
to increased cardiovascular risk. We have previously demonstrated that the increase in 
circulating levels of T3 following substitution of LT3 for LT4 results in significant decrease in 
total and LDL cholesterol, 10.9% and 13.3%, respectively (40). No significant differences in 
cholesterol or in lipoprotein levels were demonstrated as a result of LT3/LT4 therapy, 
presumably because of the heterogeneity of the study populations. Our study design offers the 


28 
 
unique opportunity to assess the effects of LT3/LT4 combination therapy in patients who 
transitioned from euthyroidism to hypothyroidism without the confounder of residual thyroid 
hormone production or a prolonged course of thyroid dysfunction. We will compare the levels of 
total, LDL, and HDL cholesterol at baseline and at three and six months following surgery 
between LT4 and LT3/LT4-treated patients. Additionally, by longitudinally assessing serum 
lipids in the same patient before and after thyroidectomy while on LT4 or LT3/LT4 therapy, we 
will be able to obtain information whether surgical hypothyroidism, despite adequate 
replacement results in significant changes in lipid levels, and if LT3/LT4 therapy this can be 
prevent these changes. The data gathered in this aim will thus provide high value (due to the 
strengths of the study design) point estimates to evaluate the effect size of the LT3/LT4 on lipid 
metabolism. Expected results. We predict that the LT3/LT4 therapy will result in a measurable 
decrease in total and LDL cholesterol compared to LT4 treatment arm, which in turn will show 
an increase compared to baseline. 
 
3.4 Exploratory aims: to evaluate the changes in ThyPRO-39, a thyroid specific quality 
of life instrument, and the role of the Thr92Ala D2 polymorphism in post-surgical 
thyroidectomy patients treated with LT4 or LT3/LT4 combination therapy. 
 
Quality of Life. A deterioration in quality of life is a common complaint of hypothyroidism (4-8), 
which persists despite adequate replacement therapy (3). While few studies have indicated 
improvement in indices of quality of life in patients treated with LT3/LT4 combination therapy, 
the results are far from definitive. Aside study design limitations, some studies used quality of 
life instruments which lack of specificity for thyroid dysfunction related symptoms. To address 
this shortcoming, we plan to use the ThyPRO-39, a validated thyroid-specific quality of life 
instrument which is considered the gold standard for the assessment of thyroid related 
symptoms and overall well-being (77-80). We have secured the collaboration of Dr. Watt, the 
creator of this instrument, who will contribute in analyzing the data (see letter of support). We 
are confident that we will be able to obtain a point estimate difference between the two 
treatment groups which will enable us to justify the development of a larger adequately powered 
study to detect clinically significant differences in quality of life. 
D2 Polymorphism. Epidemiologic, in vivo, and in vitro data support the hypothesis that the 
Thr92Ala D2 polymorphism (81) causes a reduction in the hormonal signaling due to a decrease 
in conversion of T4 into T3 (82-86). The Thr92Ala D2 polymorphism is associated with worse 
quality of life at baseline in hypothyroid patients, who responded better to LT3/LT4 combination 
therapy (39), but the results are not conclusive (87), and no prospective study has been 
performed to assess its role in the response to combination therapy. The prevalence of the 
minor Ala92 allele (81) will enable a Mendelian randomization, and we expect that 50% of 
the study population will be a carrier as heterozygous or homozygous. We do not expect to be 
able to detect a significant difference in any of the study outcomes as a consequence of the 
Thr92Ala D2 status, but the data gathered in this proof-of-concept study will enable to measure 
the point estimate for the modulatory role of the Thr92Ala D2, and if deemed relevant and 
feasible to design an adequately powered study. Genomic DNA extraction and genotyping will 
be performed in the Department of Endocrine  lab. Briefly, genomic DNA isolated from whole 


29 
 
blood is amplified and genotyped using a SYTO 9 based PCR master mix containing primers 
specific to the DIO2 
rs225014 (Thr92Ala) variant. PCR amplification and genotyping by small amplicon high-
resolution melting (88) will be performed on the Applied Biosystems QuantStudio 3 real-time 
PCR system. 
4 STUDY DESIGN 
This is a two arm, parallel, double blind placebo controlled (both arms will receive active 
medication) proof of concept study. Thirty patients will be enrolled and allocated 1:1 to the 
LT4 alone or to the LT3/LT4 combination regimen. Due to the exploratory and preliminary 
nature of the funding mechanism (R21) and FOA (Pilot and Feasibility Clinical Trials in 
Diabetes, and Endocrine and Metabolic Diseases), the study is geared toward gathering a 
large amount of preliminary data in a relatively small number of study participants (dense 
phenotyping). The acquisition of point estimates of the endpoints will then enable us to 1) 
justify the execution of a large study (go/no-go); 2) define primary and secondary outcomes; 
3) adequately power a large, multicenter study able to demonstrate clinically relevant 
differences in the selected endpoints. 
5 PATIENT SELECTION 
A maximum of 60 adult patients will be screened in this study, in order to have a least 30       
patients completed. 
The Principal Investigator will give his approval to the participation of each subject in the 
study on the basis of acceptable medical history and findings in the physical examination 
and laboratory investigations which comply with the inclusion/exclusion criteria below. 
5.1 Inclusion Criteria 
A potential subject must meet all of the following inclusion criteria to be eligible to 
participate in the study. 
5.1.1 Clinical indication for total thyroidectomy  
5.1.2 Euthyroid (TSH at screening> 0.45<4.5 mIU/mL) 
5.1.3 Indication to total thyroidectomy for benign goiter or thyroid cancer not requiring                 
suppressive thyroid hormone therapy 
5.1.4 Age 18-89 years of age  
5.1.5  Males and females 


30 
 
5.2 Exclusion Criteria 
A potential subject who meets any of the following exclusion criteria is ineligible to 
participate in the study.  
5.2.1 Weight <50 or >150 Kg; 
5.2.2 Graves’ disease  
5.2.3 Use of thyroid hormone therapy use of thyroid hormone therapy or thyroid   
supplements (at screening) except for multinodular goiter;  
5.2.4  Indication for thyroid hormone suppressive therapy following surgery 
5.2.5  Uncontrolled arterial hypertension. (Stage 2 or greater on medication); (>140/90 
mmHg at screening while on medication (patients with hypertension controlled by 
therapy will be allowed to participate). 
5.2.6 Cardiovascular disease: congestive heart failure; unstable coronary artery disease 
(angina, coronary event, or revascularization within 6 months); atrial fibrillation, 
arrhythmia or ventricular arrhythmia, 
5.2.7 Pregnancy, breastfeeding, or planned pregnancy within six months from the   
thyroidectomy 
5.2.8  History of major depression or psychosis;  
5.2.9  Uncontrolled diabetes (HbA1c > 8% or fructosamine < 325 mcmol/l in substitution 
of HbA1c to reflect recent improvement in diabetes control at screening 
5.2.10   Conditions that in the opinion of the PI may impede the successful completion of       
the study 
Patients on statin treatment will be allowed to participate in the study and the treatment will 
remain unchanged throughout the study. 
6 STUDY ENTRY AND WITHDRAWAL PROCEDURES 
6.1 Study Entry Procedures 
6.1.1 Required Pre-Registration Screening Tests and Procedures 
The study participants will be recruited primarily among patients attending the 
multidisciplinary endocrine tumor program at VCU, although self-referral from 
ClinicalTrials.gov will be allowed. The study will also be publicized among local 
endocrinologists and ENT surgeons. Self-referral will be allowed.     


31 
 
During the screening visit, the following procedures will be performed: informed 
consent, history and physical examination performed by a trained physician, weight 
and vital signs recorded by a trained physician or nurse.  
Registration Process 
After obtaining informed consent and all initial screening visit procedures, patients 
will participate in one screening visit, one dose adjustment outpatient visit, and three 
inpatient overnight admissions (referred as phenotyping visits) 
 
6.2 Study Withdrawal Procedures 
6.2.1 A patient is free to withdraw from the study for any reason, at any time, without 
reason for doing so and without any penalty of prejudice. 
6.2.2 A patient may be removed from treatment for one of the following criteria: 
6.2.3 The study physician thinks it is necessary for the health and safety of the patient.  
6.2.4 Principal Investigator’s decision to discontinue the study. 
6.2.5 The patient is non-adherent with the protocol  
6.2.6 If an adverse event (including worsening of the concomitant illness) develops which 
is considered by the Investigator as incompatible with continuation of the study  
6.2.7 Administrative reasons that require the patient to withdrawal 
6.2.8 If pregnancy develops 
6.2.9 Lost to follow-up 
6.2.10 Patient death 
6.2.11 All available data will be collected if feasible.  The reason for discontinuation should 
be documented in the case report form (CRF). 
If a patient decides to withdraw from the study, any information and specimens 
already collected will be handled according the following algorithm. Patients who 
withdrew consent before the end of their involvement will not have their data used. 
 
 
 
 


32 
 
Table 2: Effects of Withdrawal on Data Collected.   
Timing of Withdrawal 
Action 
After the screening visit, before baseline 
Data collected will not be deleted, but no 
additional information regarding the patient 
will be obtained. 
After the baseline visit before 6 week Visits  Data collected will not be deleted, but no 
additional information regarding the patient 
will be obtained. Information gathered can 
still be used in analyses. 
After the 6 week Visit before Month 3  
Data collected will not be deleted, but no 
additional information regarding the patient 
will be obtained. 
After Month 3 Visit before 6 Month 
Data collected will not be deleted, but no 
additional information regarding the patient 
will be obtained. 
 
7 PREMATURE TERMINATION 
7.1  
The sponsor has the right to terminate the trial prematurely if there are any relevant 
medical or ethical concerns, or if completing the trial is no longer practicable. If such action is 
taken, the reasons for terminating the trial must be documented in detail.  All trial subjects still 
under treatment at the time of termination must undergo a final examination, which must be 
documented.  
8 TREATMENTS 
8.1 Investigational /non Investigational Products 
The following medications will be used in this study: 
• 
Levothyroxine (LT4) 
• 
Liothyronine (LT3) 
• 
Placebo (sugar pill)                                                                                          
(Medisca empty gelatin capsules size 00 manufactured by CapsuleDepot) 
The VCU Investigational Drug Pharmacy will over-encapsulate the Investigational Pharmacy will 
over-encapsulateLT4 plus placebo, or LT4 plus 5 mcg LT3 in “AM” and “PM” color coded 
capsules.    


33 
 
The pharmacy will create the over-encapsulating tablets and making matching placebo capsule 
placebo distinguish the AM and PM doses They will use; dextrose, USP (anhydrous) 
manufactured by Medisca empty gelatin capsules size 00 manufactured by CapsuleDepot 
The placebo capsules is used to assist in the blinding process, It will allow that two capsules to 
be given as one of the randomized study drug is one drug Levothyroxine alone. The placebo will 
make the number of capsules (2) the same dose Levothyroxine and Lithothyroxine dose 
combination        
 
8.2 Study Dosing Group  
In this study, Levothyroxine (LT4) and placebo (a look-alike inactive substance, a “sugar pill”) 
will be compared to Liothyronine/levothyroxine (LT3/LT4) combination therapy.  Levothyroxine 
(LT4) and Liothyronine ( LT3) are drugs approved by the U. S. Food and Drug Administration 
(FDA).  
 
There will be thirty (30) subjects enrolled into the study. They will be randomly assigned 1:1 into 
one of two study-dosing groups: 
Table 3:  Randomization Dosing Table  
 Study Group 
Number of Subjects 
LT4 group + Placebo 
Fifteen Subjects 
LT4/LT3 group 
Fifteen Subjects 
 
8.3 Dosage and administration  
Study Dosing   
 
Patients in the LT4 group will be started at a dose of 1.6 mcg/Kg (52), while patients assigned to 
LT4/LT3 group will have 25 mcg of LT4 substituted with 5 mcg LT3 twice daily, to mimic the 
average daily T3 production form the thyroid (36). For patients taking oral Semaglutide the initial 
levothyroxine dose will be reduced to 1.2 mcg/Kg (-25 mcg in case of randomization to the 
levothyroxine/liothyronine group) to correct for increase in absorption. The VCU Investigational 
Pharmacy will over-encapsulate LT4 plus placebo, or LT4 plus 5 mcg LT3 in “AM” and “PM” 
color coded capsules. Patients will be instructed to take the AM drug first thing in the morning 
with water only, and to wait at least 30 minutes before taking other medications coffee or 
breakfast. The PM dose will be taken at least 30 minutes before dinner. Dose adjustments will 
be performed at the 6-week and 3-month follow up visits by an unblinded endocrinologist (Dr. 
Madan) aiming to achieve and maintain a target TSH within the normal range and within ± 0.5 
mcIU/ml from the baseline (pre-surgery) TSH, according to the scheme in Table 1. Doses will be 
rounded to the nearest available formulation. No changes will be made in LT3.  


34 
 
Patients and their healthcare providers will be encouraged to inform the study team of any 
change in medications. An information card containing a basic description of the protocol, study 
medications, and contact information of the PI and study coordinator will be given to the study. 
participants with instructions to show it at any encounter with healthcare providers for the 
duration of the study. 
 
 
 
Table 4: Dose Adjustment Table  
 
9 STUDY PROCEDURES 
STUDY VISIT PROCEDURES 
 
 
 
The entire protocol consists of five visits: one screening visit, one baseline visit, one dose 
adjustment visit, and three inpatient overnight admissions (referred as “phenotyping visits”). The 
follow up study visits will occur in a +/- 7-day window. Study participants will be admitted for 
their baseline phenotyping visit before surgery. Randomization will be performed at the time of 
the baseline visit. On discharge from the hospital, (postoperative day 1 or 2) patients will start 
the study drugs. An outpatient visit for dose adjustment will occur six weeks following surgery. 
Three months after surgery, patients will have a second overnight phenotyping visit and therapy 
adjustment. A third phenotyping visit (end of study) will be performed six months after surgery. 
The overnight phenotyping visits will be identical, except no DXA scan will be performed at 
baseline and during the 6-month post-op visit. 
The summary of the procedures is presented in the table 2 (study scheme) 


35 
 
9.1 Informed Consent 
Prior to performing any study-related procedures, the patient must sign and date an Institutional 
Review Board (IRB)-approved informed consent form (ICF).  The informed consent process 
must be thoroughly documented in the patient’s record.  
9.2 Medical History:  
The following information will be gathered from the patient and from the review of the medical 
records: 
• 
Age 
• 
Self-reported race/ethnicity  
• 
Medical History  
• 
Prior history of cardiovascular disease, diabetes, hypertension, dyslipidemia. 
• 
Prior surgical history 
• 
Social history (use of tobacco or alcohol) 
• 
History of Medication usage 
• 
Female subjects will be asked to provide a menstrual history,  
o use of contraception, and  
o self-reported pregnancy status planning for the study period.  
 
9.3 Physical Examination 
An abbreviated physical examination will be performed, and the following organ systems will be 
evaluated: 
• 
Vital signs: oral temperature and blood pressure  
• 
Neurological exam: focal deficit, resting tremor, reflexes 
• 
Lungs: sounds 
• 
Cardiovascular: rate, rhythm, murmur, peripheral pulses 
• 
Abdomen: tenderness, organomegaly 
 
9.4 Energy Expenditure Recordings  
Each of the three phenotyping visits will include an up to 24-hour recording of energy 
expenditure in the whole room calorimeter. The room calorimeter is a 10’ x 10’ x7’6” room with a 
window and transparent plexiglass wall. The room is fitted with TV, phone, hospital bed, small 
desk, a toilet behind a privacy screen and a vanity. Meals are passed through an air lock port. 
The room is fitted with Wi-Fi and the door has no lock. The enclosed space may cause some 
minimal discomfort and the ventilation can be noisy, non-dissimilar to a commercial airplane. 
Study volunteers will be instructed they can step out the room and withdraw from the study at 
any time, and there is no lock in the calorimeter’s door. Volunteers will enter the WRIC at the 
earliest at11:00 and will receive standardized meals at 13:00 (if already entered in the WRIC), 
and at 18:00, each representing 1/3 of the estimated EE with the following macronutrient 
composition: 50% carbohydrate, 20% protein, 30% fat. 


36 
 
Approximate total energy needs for weight maintenance will be calculated using the Mifflin-St. 
Jeor equation (89). EE recording will be completed at approximately 11:00 of the following day. 
 
9.5 Anthropometric data  
Height and weight will be recorded using a calibrated stadiometer. Temperature, heart rate, and 
blood pressure will be recorded by a research nurse. 
 
9.6 Blood Collection 
Venous Blood Sample Collection  
We will insert a needle in a vein to collect blood samples at specified times. Study subjects will 
undergo one venipuncture during each of the study visits. Altogether, five blood samples will be 
collected throughout the study for a total of approximately one and a half cup of blood.  All the 
samples collected will be for the research study, except for the measurement of TSH that will be 
used to adjust the therapy.   We will store and analyze your samples for lipids (cholesterol, HDL, 
triglycerides), Thyroid stimulating Hormone TSH (determinations for dose adjustments), Free T4 
and total T3. TPO antibodies and HbA1c or fructosamine < 325 mcmol/l in substitution of HbA1c 
to reflect recent improvement in diabetes control (the latter for patients with diabetes) will be 
collected at the screening visit to help determine the presence of autoimmune thyroid disease 
and, limited to patients with diabetes, the control of the disease. Blood samples will be collected 
at screening, baseline (pre-surgery), 3-month and 6-month study visits. 
 
We will collect two 5 mL of blood will be collected in a Na-EDTA tube (purple top) at the baseline 
visit to obtain HbA1c and to extract genomic DNA. Approximately 20 mL of blood will be collected 
in SST tubes with (no additives except serum separator) each session for TSH, thyroid hormones 
(total T3 and free T4), serum lipids and storage.  No more than 320 mL of blood will be collected 
over the course of the five sessions. Serum will be separated by centrifugation, aliquoted in 1 mL 
cryovials and stored in -80⁰C freezers in the Department of Endocrine laboratory in Sanger Hall. 
Samples will be stored as described above for future analyses for studies. The Thr92Ala D2 
polymorphism will be analyzed in the Department of Endocrine laboratory. Dr. Ni will supervise 
the performance of these analyses. 
9.7 Accelerometers  
 The accelerometers are sensing devices that measure a moving object's acceleration and can 
detect frequency and intensity of human movement. They are very similar to “Fitbit” or other 
exercise recording devices.  Maybe done depending upon availability  
 
9.8 Genetic Material 
 
Genetic material will be collected during the study to study whether common gene variations 
called “Single Nucleotide Polymorphisms” (SNPs) in gene that regulate the thyroid hormone 


37 
 
signaling affect the response to the therapy. We do not plan to screen for genetic disease, and 
the information collected are without clinical interest, thus the information will not be provided to 
the volunteers. No genome wide association study will be performed, and the genetic material 
will be disposed of at the end of the study. Study volunteers can opt out the collection of genetic 
material.  
 
9.9 Quality of Life assessment 
 
Study participants will be administered ThyPRO-39, a thyroid specific quality of life instrument 
at the baseline (pre-surgery), 3-month and 6-month visit. This questionnaire helps the 
researchers to measure the intensity of the symptoms associated with hypothyroidism, and their 
changes in relation to the therapy. Some individual may experience discomfort by gaining 
introspection in their condition.  
 
9.10 DXA Scan (Dual-energy x-ray Absorptiometry): 
DXA stands for dual-energy x-ray absorptiometry (also known as a DEXA scan). A simple, 10-
minute test takes a comprehensive snapshot of your exact breakdown of bone, fat tissue, and 
muscle mass. The DXA scan is the most accurate and precise body fat test available. There are 
not any special preparations needed, except to stop taking any calcium supplements for 24 
hours before the test. Study participants are requested to lay still on a table while a sensor 
(similar to an X-ray machine) moves over the body from the head to the feet. Wear comfortable 
clothing. Study volunteers will undergo (DXA scan) at the baseline and six-month visits. The 
only potential risk associated with DXA scan is the exposure to radioactivity. 
 
 
9.11 Echocardiogram (echo) 
An echocardiogram will be performed at the baseline, three and six-month visits to assess the 
myocardial structure and ejection fraction.   
 
10     STUDY VISITS 
10.1   Overall study schedule  
Study schedule summarized (Table 1) 
 
10.2   Screening/Inclusion  
 (Screening Visit) 
Trained Endocrinologists and study staff will conduct the screening Visit 


38 
 
Study Identifiers  
At screening, each volunteer will be assigned a sequential volunteer ID number (EMT-01M25, 
EMT-02F27, etc) that will indicate study identifier, sequential number of screening, sex, age). 
The suffix “E” will be applied to volunteer who met the inclusion criteria and were enrolled in the 
study. The volunteer ID number will be used for all study related procedures. The key to the 
volunteer ID number will be maintained by the study coordinator and will be kept in a secure 
location behind a locked door (Sanger Hall, 8th Floor, Room 8-066). Only allowed investigators 
on the study roster will have access to the key (upon request). The key will be destroyed at the 
end of study following VCU policy. 
 
Screening Visit will include: 
 
• 
Informed Consent (section 9 (9.1)) 
 
• 
Anthropometric information, which include measures of height, weight, 
temperature, and body composition and blood pressure.(section 9 (9.5)) 
   
• 
A physical exam will be performed by the study physician (section 9 (9.3)) 
 
• 
The study team will collect the following information (section 9 (9.2)) 
o demographics,  
o Medical history  
o Prior surgical history,  
o social history,  
o history of medication usage;  
 
• 
Female subjects will be asked to provide a menstrual history,  
o use of contraception, and  
o Self-reported pregnancy status for the study period.  
 
• 
Blood sampling: (section 9(9.6)) 
o Thyroid peroxidase antibody (TPO antibodies)  
o Thyroid Stimulating Hormone (TSH)  
o HgA1c (for subjects with a history of diabetes) 
• 
Review the inclusion /exclusion to determine eligibility section (5 5.1 and 5.2) 
 
 
The Endocrinologist will determine study eligibility. Eligible subjects will proceed to three 
identical overnight Phenotyping Visits and one outpatient Dose Adjustment Visit:  
o (Visit 1)  Baseline  


39 
 
o (Visit 2)  Three month after surgery  and  
o 6 Week Dose Adjustment Visit 
o (Visit 3)  Six month Visit  End of study    
 
10.3   Phenotype Visit 1 (Baseline) 
Once the surgical thyroidectomy date has been determined, subjects will be scheduled for 
the Phenotype (Visit 1) Baseline Visit 
10.3.1 Two (2) days prior to the Phenotype Visit 1 Baseline   
Subjects will be instructed to: 
o refrain from strenuous exercise  
o Remain on a regular diet  
10.3.2 Prior to Surgery Phenotype Visit 1 Baseline  
Subjects will be admitted to the hospital on the Clinical Research Services Unit for an 
inpatient stay in the whole room indirect calorimeter (WRIC) prior to Thyroidectomy 
surgery (Standard of care) 
o Randomization will be performed  
 
o The following will be performed in the am Prior to Entry into the WRIC  
o An abbreviated history and physical examination.  
o Echocardiogram recorded,  
o Administration of ThyPRO-39.  
o Accelerometers Fitting - subject will be fitted with five (one on each limb 
plus chest) to record spontaneous movements. (maybe done depending 
upon availability)  
o DXA scan 
o  
 
o The subject will enter the WRIC at 11:00 am 
 
o Dietary Meals  
o The study will provide Standardized Meals.   
 
o Standardized Meals will be served at 13:00 (if already entered in the WRIC), and 
at 18:00, each representing 1/3 of the estimated EE with the following 
macronutrient composition: 50% carbohydrate, 20% protein, 30% fat. 
Approximate total energy needs for weight maintenance will be calculated using 
the Mifflin-St. Jeor equation (89). EE recording will be completed at 
approximately 11:00 of the following day,  


40 
 
 
o EE recording will be completed at approximately 11:00 of the following day, 
 
o Blood sampling: TSH, Genomic DNA, Free T4, Free T3, Lipids, serum for     
storage    
o Dispense Study Medication prior to discharge 
 
On discharge from the hospital, (postoperative day 1 or 2) patients will start the study drugs  
 
10.4 Six Week Post Surgery  
An outpatient visit for dose adjustment will occur six weeks following surgery. 
o An abbreviated history and physical examination.  
o Blood sampling: TSH, serum for storage    
o Dose Adjustment  
o Dispense Study Medication prior to discharge 
 
 
10.5 Phenotype Visit 2 (Month 3) 
Three months after surgery, patients will have a second overnight phenotyping visit and 
Medication adjustment.   
 
o The following will be performed in the am Prior to Entry into the WRIC  
o An abbreviated history and physical examination 
o Pill count  
o Echocardiogram recorded,  
o Administration of ThyPRO-39.  
o Accelerometers Fitting - subject will be fitted with five (one on each limb 
plus chest) to record spontaneous movements. (maybe done depending 
upon availability)  
o  
 
o The subject will enter the WRIC at 11:00 am 
 
o Dietary Meals  
o The study will provide Standardized Meals.   
 
o Standardized Meals will be served at 13:00 (if already entered in the WRIC), and 
at 18:00, each representing 1/3 of the estimated EE with the following 
macronutrient composition: 50% carbohydrate, 20% protein, 30% fat. 
Approximate total energy needs for weight maintenance will be calculated using 
the Mifflin-St. Jeor equation (89). EE recording will be completed at 
approximately 11:00 of the following day,  
 


41 
 
o EE recording will be completed at approximately 11:00 of the following day, 
 
o Blood sampling: TSH, Free T4, Free T3, Lipids, serum for     storage    
o Dispense Study Medication prior to discharge 
 
Note:  No DXA scan will be performed during the 3-month post-op visit. 
 
 
10.6 Phenotype Visit 3 (Month 6) 
Six months after surgery a third phenotyping visit (end of study).  
 
o The following will be performed in the am Prior to Entry into the WRIC  
o An abbreviated history and physical examination 
o Pill count  
o Echocardiogram recorded  
o Administration of ThyPRO-39  
o Accelerometers Fitting - subject will be fitted with five (one on each limb 
plus chest) to record spontaneous movements. (maybe done depending 
upon availability)  
o DXA scan 
o  
 
o The subject will enter the WRIC at 11:00 am 
 
o Dietary Meals  
o The study will provide Standardized Meals.   
 
o Standardized Meals will be served at 13:00 (if already entered in the WRIC), and 
at 18:00, each representing 1/3 of the estimated EE with the following 
macronutrient composition: 50% carbohydrate, 20% protein, 30% fat. 
Approximate total energy needs for weight maintenance will be calculated using 
the Mifflin-St. Jeor equation (89). EE recording will be completed at 
approximately 11:00 of the following day,  
 
o EE recording will be completed at approximately 11:00 of the following day, 
 
o Blood sampling: TSH, Free T4, Free T3, Lipids, serum for storage   
  
o Collect Medication prior to discharge 
 
10.7 End of study Treatment  
At the end of the trial the subjects care will be transferred to their endocrinologist or primary 
care provider. We will prescribe three-month supply of the levothyroxine or levothyroxine-


42 
 
liothyronine combination therapy, based on the subject’s preference since both drugs are 
approved for the treatment of hypothyroidism. The subjects insurance will be responsible for 
the cost of the prescription since the study is completed. 
 
 
11     STUDY RECRUITMENT AND RETENTION 
 
11.1 Recruitment                                                                                     
11.1.1     Recruitment of Women, children and minority individuals study   
In this study, we will recruit exclusively adult women and men (age > 21). This choice is 
driven by scientific reasons because the prevalence of hypothyroidism is highest in the adult 
population. The study design precludes the recruitment of children since the differences in the 
biomarkers between adults and children would impede the interpretation of the data collected. 
Furthermore, since this proof-of-principle study the participation of minors in the study would 
provide little additional information. We expect an overrepresentation of women in the study, 
reflecting the higher prevalence of hypothyroidism in females. We will encourage the 
recruitment of minorities, and the ethnic composition of the accrual table reflect the population 
attending the outpatient clinics of Virginia Commonwealth University Medical Center. 
 
11.1.2     Recruitment and retention plan 
The recruitment will be primarily performed from patients undergoing evaluation in the 
multidisciplinary thyroid neoplasia clinic and through ENT at Virginia Commonwealth University, 
but the study information will be disseminated among local endocrinologists, and self-referral 
will be allowed. Additionally, the study will be disseminated through Adult Endocrinologists and 
Surgeons performing thyroidectomy at VCU (ENT and Endocrine Surgeons) will be made aware 
of the study hypothesis, design, and potential benefits for the participants. 
 
11.2 Retention                                                                                     
Study participants will not receive compensation, but the study visits, including TSH assay for 
therapy adjustment will be performed free of charge. Additionally, the study medications will be 
dispended free of charge for the duration of the study (six months). Patients will be provided 
with meal and parking coupons for the study visits. Patients will also be informed of the results 
of their phenotype studies, including body composition, energy expenditure, and 
echocardiogram. These benefits should provide sufficient incentive to assure retention of the 
study participants. 


43 
 
12     DATA AND SAFETY MONITORING PLAN (DSMP)  
Data and Safety Monitoring Plan (DSMP):  
The research team will develop a complete DSMP for review by the NIH. The PI, Dr. Angeliki 
Stamatouli, a physician board-certified Endocrinology, Diabetes and Metabolism, and Internal 
Medicine will assume responsibility to ensuring the overall safety of protocol participants.  
 
An independent Data and Safety Monitoring Board (DSMB) will be responsible for monitoring 
the safety of participants and the data associated with the proposed study.                                   
The DSMB will be comprised of a physician, a pharmacist, and biostatistician. One member of 
the DSMB will be selected as the Committee Chair and will be responsible for generating a 
written summary of the content of each quarterly meeting. Potential adverse events will be listed 
in the IRB-approved protocol and in the consent form. A record of adverse events will be 
retained in a study binder for review by the study team, the independent DSMB, and the IRB. 
The classification of adverse events will be as follows: 1) Mild Severity, discomforts that do not 
disrupt daily activities, or adverse events in which no therapy or only symptomatic therapy is 
required); 2) Moderate Severity (discomfort sufficient to modify normal daily activity, or adverse 
events requiring specific therapy that is more than symptomatic; 3) Serious Severity (illness or 
injury resulting in inability to work or to perform normal daily activities, life-threatening events or 
death). All adverse events will initially be evaluated by the PIStamatouli), a physician who is 
board-certified in Endocrinology and Internal Medicine. Additionally, the unblinded physician 
(Madan) and the Cardiologist (Abbate) will be available to provide insight on the severity and the 
potential association with the study drugs and dosage. Those events classified as moderate or 
severe will be reported to DSMB Committee Chair for review within 24 hours. The entire DSMB 
will meet to review all serious adverse events, should they occur. In addition, all serious adverse 
events, both anticipated and unanticipated, will be reported to the IRB within 48 hours (and to 
the NIH within a timeframe consistent with the policy of the institute). Additionally, a summary of 
all adverse events will be submitted to the Institution IRB annually as part of the protocol’s 
continuing review. 
13    CLINICALTRIALS.GOV REQUIREMENTS:  
This application includes a trial which requires registration in ClinicalTrials.gov. As is required, 
this trial will be registered upon approval from the institution’s IRB. 
Dissemination of study results through ClinicalTrials.gov registration and reporting at a minimum 
will include the following components: The Principle Investigator (PI) will be responsible for 
ensuring compliance with ClinicalTrials.gov requirements for this project. The PI or his/her 
designee will register the trial prior to enrolling the first subject. Once a record is established, the 
PI will confirm accuracy of record content; resolve problems; and maintain records including 
content update and modifications. The PI will also be responsible for aggregate results reporting 
and Adverse Event reporting at the conclusion of the project. I certify that this submission 
contains an Applicable Clinical Trial (ACT) and that I will ensure compliance with registration 
and results reporting submissions to ClinicalTrials.gov as required under the FDA Amendment 
Act of 2007 (FDAAA) and the Final Rule (42CFR Part 11).  For all clinical trials in scope of the 
Policy, the informed consent will include the FDA- required statement related to 


44 
 
ClinicalTrials.gov: “A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law. 
14    ADVERSE EVENTS  
Any adverse reaction occurring during the study either observed by the physicians or nurses or 
reported by the patient will be recorded. Anticipated adverse events that will not be reported to 
the IRB include the pain and bruise associated with needle stick, and abnormal laboratory 
results that are found as a part of the screening blood work and lead to exclusion from the 
study, but will receive appropriate follow-up and referral to the primary care provider. Also other 
incidental serious adverse events unrelated to the study (such as trauma resulting from motor 
vehicle accidents or sport activities) will not be reported to the IRB. Serious adverse events: All 
serious adverse events related or possibly related to the research protocol, i.e. cardiovascular 
events, psychiatric events, intravenous catheter or venipuncture site infection/bleeding, and 
thrombophlebitis will be reported to the IRB as soon as possible, but no later than seven days of 
death or life threatening serious adverse event or within fifteen days after the occurrence of all 
other forms of serious adverse events. A serious adverse event is any adverse drug experience 
that: 1) Results in death; 2) Is life threatening; 3) Results in hospitalization or prolongs 
hospitalization; 4) Results in persistent or significant disability or incapacity; 5) Results in 
congenital anomaly or birth defect; 6) Results in a condition, which in the judgment of the 
investigator represents a significant hazard. 


45 
 
15 ADVERSE EVENTS: DEFINITIONS AND REPORTING 
REQUIREMENTS 
15.1 Definitions 
15.1.1 Adverse Event (AE) 
AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
15.1.2 Serious AE (SAE)  
An AE is considered “serious” if, in the view of the investigator, it results in any of 
the following outcomes: 
• 
death, 
• 
a life-threatening AE (An AE is consider “life-threatening” if, in the view of the 
investigator, its occurrence places the patient or subject at immediate risk of 
death. It does not include an AE that, had it occurred in a more severe form, 
might have caused death.), 
• 
inpatient hospitalization or prolongation of existing hospitalization, 
• 
a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
• 
a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
15.1.3 Unanticipated Problem (UP) 
Unanticipated problems include any incident, experience, or outcome that meets all 
of the following criteria: 
• 
unexpected (in terms of nature, severity, frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• 
related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
• 
suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 


46 
 
15.1.4 AE Description and Grade 
The descriptions and grading scales found in the revised Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. 
15.1.5 AE Expectedness 
AEs can be ‘Unexpected’ or ‘Expected’. 
Expected AEs are listed in section 8.2 below. 
Unexpected AEs are those AEs occurring in one or more subjects participating in 
the research protocol, the nature, severity, or frequency of which is not consistent 
with either: 
• 
The known or foreseeable risk of AEs associated with the procedures involved 
in the research that are described in (a) the protocol-related document, such as 
the IRB-approved research protocol, any applicable investigator brochure, and 
the current IRB-approved informed consent document, and other relevant 
sources of information, such as product labeling and package inserts; or 
• 
The expected natural progression of any underlying disease, disorder, or 
condition of the subject(s) experiencing the AE and the subject’s predisposing 
risk factor profile for the AE. 
15.1.6 AE Attribution 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely – The AE is doubtfully related to the study treatment. 
• 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
15.2 Known AEs List 
Table 3: Known AEs/Risks. 
Research-related risks in this study include those associated with study procedures, namely 
blood drawing, study medications, radiation exposure, and dissemination of PHI, including 
genetic data. 
No significant risk can be expected from the whole room indirect calorimeter, echocardiogram. 
Some individuals may experience anxiety during the stay in the indirect calorimeter. Potential 
additional risks are associated with the collection of genetic material and the possible 


47 
 
infringement of the study participants’ privacy with dissemination of protected health 
information (PHI).  
 
Table 5 Study Risk Assessment 
Assessment/Procedure 
Possible AEs/risks 
Energy 
Expenditure 
recording 
The only risk is anxiety or discomfort due to extended period of fasting. 
06:00 PM until the end of the whole room indirect calorimeter recording 
at 11:00 AM of the next day), about 8-hours overnight fasting and 4 hours 
fasting during the study) 
Anxiety space available in the whole room indirect calorimeter.  
claustrophobia 
Echocardiograph 
Allergy or sensitive to adhesive or latex and may experience skin rash 
(dermatitis) from the electrodes.  
DXA Scan  
A  low dose of X-ray radiation comparable to 1/10 of the radiation from a 
chest x-ray.   
Blood collection 
There may be pain at the site where the catheter is inserted, and some 
bruising and very rarely infection may occur. Some people may 
experience nausea or faint when the catheter is inserted or when they see 
blood. Bandages used to cover the catheter site may cause a skin rash 
(dermatitis) in some people who are allergic or sensitive to adhesive or 
latex 
Quality of Life (QoL) 
questionnaires 
Participants may experience some emotional discomfort as they assess 
their perceived quality of life 
Genetic Risk 
 Infringement of the study participants’ privacy with dissemination of 
protected health information (PHI).  Breech of confidentiality  
 
Pregnancy: Pregnancy is not considered an AE, although a patient will be withdrawn from 
the study if a pregnancy occurs and the visit will be completed. The pregnancy must be 
immediately reported to the Principle investigator. Additional follow-up may be required. 
15.3 Time Period and Grade of AE Capture 
Collection of AEs will start immediately following signing of the ICF and will continue 
throughout the study.  Illnesses present before the patient signs the informed consent form 
(ICF) are considered pre-existing conditions and are documented on the medical history 
worksheet and in the Case Report Form.  Pre-existing conditions that worsen during the 
study are entered on the AE case report form.  


48 
 
Table 6  Adverse Event Grades Based on the Common Terminology Criteria for  
              Adverse Events  
 
Grade 
Description 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated 
2 
Moderate: minimal, local, or noninvasive intervention indicated; limiting age appropriate 
instrumental activities of daily living (eg, preparing meals, shopping for groceries or 
clothes, using the telephone, and managing money) 
3 
Severe: severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living (eg, bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden) 
4 
Life-threatening: Life-threatening consequences; urgent intervention indicated 
5 
Death: Death related to AE 
Source: National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 
4.03 (CTCAE 2010). 
 
Table 7: Adverse Event Grading For Known AE/Risks Using CTCAE Guidelines 
 
Adverse 
Event 
Description 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 
5 
Anxiety 
A disorder 
characterized by 
apprehension of 
danger and 
dread 
accompanied by 
restlessness, 
tension, 
tachycardia, and 
dyspnea 
unattached to a 
clearly 
identifiable 
stimulus. 
Mild 
symptoms; 
intervention 
not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self-care 
ADL; 
hospitalization 
indicated 
Life-
threatening 
consequences
; 
urgent 
intervention 
indicated 
N/A 
 
 
 
 
 
 
 
Palpitation 
A disorder 
characterized by  
an unpleasant  
sensation of 
Mild 
symptoms; 
intervention 
not 
indicated 
Intervention 
indicated 
N/A 
N/A 
N/A 


49 
 
irregular and/or 
forceful beating 
of the heart. 
Pre-syncope 
A disorder 
characterized by 
an episode of 
lightheadedness 
and dizziness 
which may 
precede an 
episode of 
syncope. 
N/A 
Present (e.g., 
near fainting) 
N/A 
N/A 
N/A 
Syncope 
A disorder 
characterized by 
spontaneous 
loss of 
consciousness 
caused by 
insufficient blood 
supply to the 
brain. 
N/A 
N/A 
Fainting; 
orthostatic 
collapse 
N/A 
N/A 
Pain of Skin 
A disorder 
characterized by 
a sensation of 
marked 
discomfort in the 
skin. 
Mild pain 
Moderate pain; 
limiting 
instrumental 
ADL 
Severe pain; 
limiting self care 
ADL 
N/A 
N/A 
Contact 
Dermatitis 
A disorder 
characterized 
by a rash 
and/or itching 
of the skin 
where 
adhesive or 
latex was in 
contact with 
the skin. 
Asymptomatic 
or mild 
symptoms; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Moderate; 
minimal, local 
or noninvasive 
intervention 
indicated; 
limiting 
age-
appropriate 
instrumental 
ADL 
N/A 
N/A 
N/A 
Bruising 
A finding of 
injury of the 
soft tissues or 
bone 
characterized 
by leakage of 
blood into 
surrounding 
tissues. 
Localized or in 
a dependent 
area 
Generalized 
N/A 
N/A 
N/A 


50 
 
Vascular 
access 
complication 
 
TPA 
administration 
into line with no 
intent for systemic 
therapy indicated 
Device 
dislodgement, 
blockage, leak, 
or malposition; 
device 
replacement 
indicated 
Pulmonary 
embolism, deep 
vein or cardiac 
thrombosis; 
intervention 
indicated (e.g., 
anticoagulation, 
lysis, filter, 
invasive 
procedure) 
Life-
threatening 
consequences 
with 
hemodynamic 
or neurologic 
instability 
Death 
Nausea 
A disorder 
characterized by 
a queasy 
sensation and/or 
the urge to 
vomit. 
Loss of appetite 
without 
alteration in 
eating habits 
Oral intake 
decreased 
without 
significant 
weight loss, 
dehydration or 
malnutrition 
Inadequate oral 
caloric or fluid 
intake; tube 
feeding, TPN, or 
hospitalization 
indicated 
N/A 
N/A 
Vomiting 
A disorder 
characterized by 
the reflexive act 
of ejecting the 
contents of the 
stomach through 
the mouth. 
Intervention not 
indicated 
Outpatient 
IV 
hydration; 
medical 
intervention 
indicated 
Tube feeding, 
TPN, or 
hospitalization 
indicated 
Life-
threatening 
consequences 
Death 
 
15.4 Procedures for Recording AEs, SAEs, and Ups 
All AEs will be documented on the AE case report form and in the patient’s medical record.  
The following attributes must be assigned:  (1) description, (2) dates of onset and 
resolution, (3) severity, (4) “serious” criteria if applicable, and (5) action taken.  The 
investigator will actively solicit this information and assess the AEs in terms of severity and 
relationship to the study.  The Investigator will treat the patient as medically required until 
the AE either resolves or becomes medically stable.  The treatment may extend beyond 
the duration of the study.  The investigator will record treatment and medications required 
for treatment on the appropriate CRF(s). 
In the event that a patient is withdrawn from the study because of an AE, the event must 
be recorded on the Termination CRF as the reason for discontinuation. 
All serious adverse events related or possibly related to the research protocol, i.e. 
cardiovascular events, psychiatric events, intravenous catheter or venipuncture site 
infection/bleeding, and thrombophlebitis will be reported to the IRB as soon as possible, 
but no later than seven days of death or life threatening serious adverse event or within 
fifteen days after the occurrence of all other forms of serious adverse events. 
 


51 
 
15.5 Routine Reporting Procedures for AEs 
Each event will be reported to the Principle Investigator once becoming aware of the 
occurrence. All AEs and SAEs will be followed until resolution, until the condition stabilizes, 
until the event is otherwise explained, whichever occurs first.  All AEs and SAEs 
documented at a previous visit/contact and designated as ongoing, will be reviewed at 
subsequent visits/contacts, where the designation may remain ongoing.  The investigator 
will ensure that the follow-up includes any supplemental investigation as may be indicated 
to elucidate at the nature and/or causality of the SAE. This may include additional 
laboratory test or investigations, histopathological examinations, or consultation with other 
health care professionals. SAEs that are ongoing at the time of the subjects final study 
visit/contact will be documented as ongoing.  
15.6 Expedited Reporting Procedures for SAEs, UPs, and DLTs 
Expedited Reporting Requirements (Events, Report Recipients, and Time Frames) 
SAEs 
UPs  
Principal Investigator1  
Principal Investigator1  
 
DSMB1 
 
IRB2 
 
 
1 Report event within 5 business days of becoming aware of the occurrence. 
2 Each UP must be reported to the VCU IRB within 5 business days of becoming aware of the 
occurrence. The report must be prepared using the “VCU IRB PROMPT REPORTING FORM,” 
found on the VCU IRB Forms Page. 
Principal Investigator 
Angeliki Stamatouli, M.D.  
804-828- 3495 
Angeliki.stamatouli@vcuhealth.org 
Massey Cancer Center DSMB 
FAX: 804-828-5406 
E-mail: masseydsmb@vcu.edu 
 
 
 
 
 


52 
 
 
15.7 Resource sharing plan  
  
The data generated by this proof-of-principle proposal will be limited due to the small 
number of patient recruited, and by the exploratory nature of the investigation. Nonetheless, 
the information gathered may be of use to other investigators who are involved in thyroid 
pathophysiology or in the development of efficacy/effectiveness trials.  
In accordance to the new Rigor and Reproducibility guidelines, we will clearly describes the 
experimental protocols in the material and methods section of the publications and maintain 
a clear and readily accessible documentation of the experimental procedures. Any research 
resources developed through this proposal will be made readily available for research 
purposes to qualified individuals within the scientific community in accordance with the NIH 
Grants Policy Statement and the Principles and Guidelines for Recipients of NIH Research 
Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources. 
Virginia Commonwealth University (Technology transfer office) has established policies for 
Material Transfer Agreements that identify what intellectual property rights will be retained 
by the University to distributed resources. 
 
 
 
 
 
 
 
 


53 
 
16 REGULATORY COMPLIANCE AND ETHICS 
16.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research (US National Commission for the Protection of Human Subjects of Biomedical 
and Behavioral Research, April 18, 1979). 
16.2 Regulatory Compliance 
This study will be conducted in compliance with: 
• 
The protocol 
• 
Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards), and 45 CFR 46 
Subparts A (Common Rule), B (Pregnant Women, Human Fetuses and Neonates), C 
(Prisoners), and D (Children) 
16.3 Institutional Review Board 
Each participating institution must provide for the review and approval of this protocol and 
the associated informed consent documents and recruitment material by an appropriate 
IRB registered with the Office for Human Research Protections (OHRP). Any amendments 
to the protocol or consent materials must also be approved. In the United States and in 
other countries, only institutions holding a current US Federal wide Assurance issued by 
OHRP may participate. 
16.4 Informed Consent Process 
Informed consent is an ongoing process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of this therapy will be provided to the 
subjects and their families. Consent forms describing in detail the study interventions/
products, study procedures, and risks are given to the subject and written documentation 
of informed consent is required prior to starting intervention/administering study product. 
Consent forms will be IRB-approved and the subject will be asked to read and review the 
document. Upon reviewing the document, the investigator will explain the research study to 
the subject and answer any questions that may arise. The subject will sign the informed 
consent document prior to any procedures being done specifically for the study. The 
subjects should have the opportunity to discuss the study with their surrogates or think 
about it prior to agreeing to participate. The subjects may withdraw consent at any time 
throughout the course of the trial. A copy of the informed consent document will be given to 
the subjects for their records. The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if 
they decline to participate in this study. 


54 
 
16.5 Subject Confidentiality and Access to Source Documents/Data 
Subject confidentiality is strictly held in trust by the participating investigators and their 
staff. This confidentiality includes the clinical information relating to participating subjects, 
as well as any genetic or biological testing. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the principal investigator. 
The principal investigator will allow access to all source data and documents for the 
purposes of monitoring, audits, IRB review, and regulatory inspections.  
The study monitor or other authorized representatives of the principal investigator may 
inspect all documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
subjects in this study. The clinical study site will permit access to such records. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


55 
 
17 DATA HANDLING AND RECORD KEEPING 
17.1 Data Management Responsibilities 
The principal investigator is responsible for: (i) the overall conduct of the investigation; (ii) 
ongoing review of trial data including all safety reports; and (iii) apprising participating sites 
of any UPs. 
Any laboratory conducting correlative studies must maintain the laboratory records and 
documentation (laboratory notebooks, laboratory protocols, print-outs, recordings, 
photographs, etc.). 
17.2 Source Documents 
Paper based source documents will be kept in secure location and only accessed by 
authorized study personnel.  Electronic records will be made available only to those 
personnel in the study through the use of access controls and encryption.  Identifiers will 
be removed from study-related data (data is coded with a key and stored in a separate and 
secure location). 
17.3 Case Report Forms  
Patient information will be collected and documented in paper based case report forms. All 
hand written entries on the case report forms (CRFs) should be made legibly in black ink. 
Errors, when made, should be corrected by drawing a single line through the incorrect 
entry (do not erase, white-out, or tape over errors) and then entering the correct data 
above the original entry. Entry corrections should be initialed and dated. Explain missing 
data with “ND” for “not determined” and “NA” used for “not applicable.” 
17.4 Study Record Retention 
As applicable, study records will be maintained a minimum of 5 years beyond: (i) the 
publication of any abstract or manuscript reporting the results of the protocol; (2) the 
submission of any sponsored research final report; or (iii) submission of a final report to 
clinicaltrials.gov. Those patients who consent to be a part of the data registry will have all 
personal identifiers kept indefinitely. Information in the databases will only be accessible to 
individuals working on the study or VCU/VCUHS officials who have access for specific 
research-related tasks.  
 


56 
 
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63 
 
Appendix A 
 
BMR formula is as follows:  
BMR (kcal / day) = 10 * weight (kg) + 6.25 * height (cm) – 5 * age (y) + s 
(kcal / day) , where s is +5 for males and -161 for females. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


64 
 
Appbendix B  
 
H LIGHTS OF PRESCRIBING INFORMATION  
These highlights do not include all the information needed to use  LEVO-T® safely 
and effectively. See full prescribing information for LEVO-T.  
  
LEVO-T® (levothyroxine sodium) tablets, for oral use   
Initial U.S. Approval: 2002  
  
WARNING: NOT FOR TREATMENT OF 
OBESITY OR FOR    
WEIGHT LOSS    
See full prescribing information for 
complete boxed warning  
•
 
  
Thyroid hormones, including Levo-T 
should not be used for the treatment of 
obesity or for weight loss.  
•
 
  
Doses beyond the range of daily 
hormonal requirements may produce 
serious or even life threatening 
manifestations of toxicity (6, 10).  
  
----------------------------INDICATIONS AND USAGE-------------------------- LEVO-T is L-
thyroxine (T 4) indicated for:  
• 
Hypothyroidism: As replacement therapy in primary (thyroidal), secondary (pituitary), 
and tertiary (hypothalamic) congenital or acquired hypothyroidism. (1)  
• 
Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression: As an adjunct 
to surgery and radioiodine therapy in the management of thyrotropin-dependent well-
differentiated thyroid cancer. (1) Limitations of Use:  
- 
Not indicated for suppression of benign thyroid nodules and nontoxic diffuse 
goiter in iodine-sufficient patients.  
- 
Not indicated for treatment of hypothyroidism during the recovery phase of 
subacute thyroiditis.  
  
-----------------------DOSAGE AND ADMINISTRATION----------------------  
• 
Administer once daily, preferably on an empty stomach, one-half to one hour before 
breakfast. (2.1)  
• 
Administer at least 4 hours before or after drugs that are known to interfere with 
absorption. (2.1)  
• 
Evaluate the need for dose adjustments when regularly administering within one hour 
of certain foods that may affect absorption. (2.1)  
• 
Starting dose depends on a variety of factors, including age, body weight, 
cardiovascular status, and concomitant medications. Peak therapeutic effect may not 
be attained for 4-6 weeks. (2.2)  
• 
See full prescribing information for dosing in specific patient populations. (2.3)  
 


65 
 
• 
Adequacy of therapy determined with periodic monitoring of TSH and/or T4 as well as 
clinical status. (2.4)  
  
-----------------------DOSAGE FORMS AND STRENGTHS-------------------  
Tablets: 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200, and 300 mcg   (3) ---------------
-----------------CONTRAINDICATIONS----------------------------  
• 
Uncorrected adrenal insufficiency. (4)  
  
------------------------WARNINGS AND PRECAUTIONS-----------------  
• 
Cardiac adverse reactions in the elderly and in patients with underlying cardiovascular 
disease: Initiate LEVO-T at less than the full replacement dose because of the 
increased risk of cardiac adverse reactions, including atrial fibrillation. (2.3, 5.1, 8.5)  
• 
Myxedema coma: Do not use oral thyroid hormone drug products to treat myxedema 
coma. (5.2)  
• 
Acute adrenal crisis in patients with concomitant adrenal insufficiency: Treat with 
replacement glucocorticoids prior to initiation of LEVO-T treatment. (5.3)  
• 
Prevention of hyperthyroidism or incomplete treatment of hypothyroidism: Proper dose 
titration and careful monitoring is critical to prevent the persistence of hypothyroidism 
or the development of hyperthyroidism. (5.4)  
• 
Worsening of diabetic control: Therapy in patients with diabetes mellitus may worsen 
glycemic control and result in increased antidiabetic agent or insulin requirements. 
Carefully monitor glycemic control after starting, changing, or discontinuing thyroid 
hormone therapy. (5.5)  
• 
Decreased bone mineral density associated with thyroid hormone over- replacement: 
Over-replacement can increase bone resorption and decrease bone mineral density. 
Give the lowest effective dose. (5.6)  
  
--------------------------------ADVERSE REACTIONS---------------------------- Adverse reactions 
associated with LEVO-T therapy are primarily those of hyperthyroidism due to therapeutic 
overdosage: arrhythmias, myocardial infarction, dyspnea, muscle spasm, headache, 
nervousness, irritability, insomnia, tremors, muscle weakness, increased appetite, weight 
loss, diarrhea, heat intolerance, menstrual irregularities, and skin rash. (6)  
  
To report SUSPECTED ADVERSE REACTIONS, contact Neolpharma, Inc. at 1-844-
200-4163 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.  
  
---------------------------------DRUG INTERACTIONS--------------------------- See full prescribing 
information for drugs that affect thyroid hormone pharmacokinetics and metabolism (e.g., 
absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) 
and may alter the therapeutic response to LEVO-T. (7)  
  
-------------------------USE IN SPECIFIC POPULATIONS---------------------  
Pregnancy may require the use of higher doses of LEVO-T. (2.3, 8.1)  
  
See 17 for PATIENT COUNSELING INFORMATION.  
 
 
  


66 
 
Revised: 12/2017   
FULL PRESCRIBING INFORMATION: CONTENTS*  
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR  
WEIGHT LOSS  
1 INDICATIONS AND USAGE  
2 DOSAGE AND ADMINISTRATION  
2.1 General Administration Information  
2.2 General Principles of Dosing  
2.3 Dosing in Specific Patient Populations  
2.4 Monitoring TSH and/or Thyroxine (T4) Levels  
3 DOSAGE FORMS AND STRENGTHS  
4 CONTRAINDICATIONS  
5 WARNINGS AND PRECAUTIONS  
5.1 Cardiac Adverse Reactions in the Elderly and in Patients   with Underlying 
Cardiovascular Disease    
5.2 Myxedema Coma  
5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal    
Insufficiency    
5.4 Prevention of Hyperthyroidism or Incomplete Treatment   of Hypothyroidism    
5.5 Worsening of Diabetic Control  
5.6 Decreased Bone Mineral Density Associated with Thyroid    
Hormone Over-Replacement    
6 ADVERSE REACTIONS 7 DRUG INTERACTIONS  
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics  
7.2 Antidiabetic Therapy  
7.3 Oral Anticoagulants  
7.4 Digitalis Glycosides  
  
  
7.5 Antidepressant Therapy  
7.6 Ketamine  
7.7 Sympathomimetics  
7.8 Tyrosine-Kinase Inhibitors  
7.9 Drug-Food Interactions  
7.10 Drug-Laboratory Test Interactions  
8 USE IN SPECIFIC POPULATIONS  
8.1 Pregnancy  
8.2 Lactation  
8.4 Pediatric Use 8.5 Geriatric Use  
10 OVERDOSAGE  
11 DESCRIPTION  
12 CLINICAL PHARMACOLOGY  
12.1 Mechanism of Action  
12.2 Pharmacodynamics  
12.3 Pharmacokinetics  
13 NONCLINICAL TOXICOLOGY  
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility  


67 
 
16 HOW SUPPLIED/STORAGE AND HANDLING  
17 PATIENT COUNSELING INFORMATION  
  
*Sections or subsections omitted from the full prescribing information are not listed.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


68 
 
1 FULL PRESCRIBING INFORMATION    
  
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS  
Thyroid hormones, including Levo-T, either alone or with other therapeutic 
agents, should not be used for the treatment of obesity or for weight loss.  
In euthyroid patients, doses within the range of daily hormonal requirements are 
ineffective for weight reduction.  
Larger doses may produce serious or even life threatening manifestations of 
toxicity, particularly when given in association with sympathomimetic amines 
such as those used for their anorectic effects [see Adverse Reactions (6), Drug 
Interactions (7.7), and Overdosage (10)].  
  
  
  
1.1 1 INDICATIONS AND USAGE Hypothyroidism  
  
LEVO-T is indicated as a replacement therapy in primary (thyroidal), secondary 
(pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.  
  
1.2 Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression  
LEVO-T is indicated as an adjunct to surgery and radioiodine therapy in the 
management of thyrotropin-dependent well-differentiated thyroid cancer.  
  
Limitations of Use:  
• 
LEVO-T is not indicated for suppression of benign thyroid nodules and 
nontoxic diffuse goiter in iodine-sufficient patients as there are no clinical 
benefits and overtreatment with LEVO-T may induce hyperthyroidism [see 
Warnings and Precautions (5.4)].  
  
• 
LEVO-T is not indicated for treatment of hypothyroidism during the recovery 
phase of subacute thyroiditis.  
  
1.3 2 DOSAGE AND ADMINISTRATION  
  
1.3.1 2.1 General Administration Information  
Take LEVO-T with a full glass of water as the tablet may rapidly disintegrate.  
  
Administer LEVO-T as a single daily dose, on an empty stomach, one-half to one hour 
before breakfast.  
 
 
 
 
 


69 
 
 
 Administer LEVO-T at least 4 hours before or after drugs known to interfere with 
LEVO-T absorption [see Drug Interactions (7.1)].   
  
Evaluate the need for dose adjustments when regularly administering within one hour 
of certain foods that may affect LEVO-T absorption [see Drug Interactions (7.9) and 
Clinical Pharmacology (12.3)].  
  
Administer LEVO-T to infants and children who cannot swallow intact tablets by 
crushing the tablet, suspending the freshly crushed tablet in a small amount (5 to 10 mL 
or 1 to 2 teaspoons) of water and immediately administering the suspension by spoon 
or dropper. Do not store the suspension. Do not administer in foods that decrease 
absorption of LEVO-T, such as soybeanbased infant formula [see Drug Interactions 
(7.9)].  
  
1.3.2 2.2 General Principles of Dosing  
The dose of LEVO-T for hypothyroidism or pituitary TSH suppression depends on a 
variety of factors including: the patient's age, body weight, cardiovascular status, 
concomitant medical conditions (including pregnancy), concomitant medications, co-
administered food and the specific nature of the condition being treated [see Dosage 
and Administration (2.3), Warnings and Precautions (5), and Drug Interactions (7)]. 
Dosing must be individualized to account for these factors and dose adjustments made 
based on periodic assessment of the patient's clinical response and laboratory 
parameters [see Dosage and Administration (2.4)].  
  
The peak therapeutic effect of a given dose of LEVO-T may not be attained for 4 to 6 
weeks.  
  
2.3 Dosing in Specific Patient Populations  
1.3.3 Primary Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty are 
Complete  
Start LEVO-T at the full replacement dose in otherwise healthy, non-elderly individuals 
who have been hypothyroid for only a short time (such as a few months). The average 
full replacement dose of LEVO-T is approximately 1.6 mcg per kg per day (for example: 
100 to 125 mcg per day for a 70 kg adult).  
  
Adjust the dose by 12.5 to 25 mcg increments every 4 to 6 weeks until the patient is 
clinically euthyroid and the serum TSH returns to normal. Doses greater than 200 mcg 
per day are seldom  required. An inadequate response to daily doses of greater than 
300 mcg per day is rare and may  indicate poor compliance, malabsorption, drug 
interactions, or a combination of these factors.  
  
For elderly patients or patients with underlying cardiac disease, start with a dose of 
12.5 to 25 mcg per day.  Increase the dose every 6 to 8 weeks, as needed until the 
patient is clinically euthyroid and the serum TSH returns to normal. The full 
replacement dose of LEVO-T may be less than 1 mcg per kg per day in elderly 
patients.  
  
 


70 
 
In patients with severe longstanding hypothyroidism, start with a dose of 12.5 to 25 mcg 
per day. Adjust the dose in 12.5 to 25 mcg increments every 2 to 4 weeks until the 
patient is clinically euthyroid and the serum TSH level is normalized.  
  
1.3.4 Secondary or Tertiary Hypothyroidism  
Start LEVO-T at the full replacement dose in otherwise healthy, non-elderly individuals. 
Start with a lower dose in elderly patients, patients with underlying cardiovascular 
disease or patients with severe longstanding hypothyroidism as described above. 
Serum TSH is not a reliable measure of LEVO-T dose adequacy in patients with 
secondary or tertiary hypothyroidism and should not be used to monitor therapy. Use 
the serum free-T4 level to monitor adequacy of therapy in this patient population. 
Titrate LEVO-T dosing per above instructions until the patient is clinically euthyroid and 
the serum free-T4 level is restored to the upper half of the normal range.  
  
1.3.5 Pediatric Dosage - Congenital or Acquired Hypothyroidism   
The recommended daily dose of LEVO-T in pediatric patients with hypothyroidism is 
based on body weight and changes with age as described in Table 1. Start LEVO-T at 
the full daily dose in most pediatric patients. Start at a lower starting dose in newborns 
(0-3 months) at risk for cardiac failure and in children at risk for hyperactivity (see 
below). Monitor for   clinical and laboratory response [see Dosage and Administration 
(2.4)].  
  
1.4 Table 1. LEVO-T Dosing Guidelines for Pediatric Hypothyroidism   
AGE  
Daily Dose Per Kg Body Weighta   
0-3 months  
10-15 mcg/kg/day  
3-6 months  
8-10 mcg/kg/day  
6-12 months  
6-8 mcg/kg/day  
1-5 years  
5-6 mcg/kg/day  
6-12 years  
4-5 mcg/kg/day  
Greater than 12 years but growth and puberty 
incomplete  
2-3 mcg/kg/day  
Growth and puberty complete  
1.6 mcg/kg/day  
a. The dose should be adjusted based on clinical response and laboratory parameters [see Dosage and 
Administration (2.4) and Use in Specific Populations (8.4)].  
Newborns (0-3 months) at risk for cardiac failure: Consider a lower starting dose in 
newborns at risk for cardiac failure. Increase the dose every 4 to 6 weeks as needed 
based on clinical and laboratory response.  
  
Children at risk for hyperactivity: To minimize the risk of hyperactivity in children, start at 
one- fourth the recommended full replacement dose, and increase on a weekly basis by 
one-fourth the full recommended replacement dose until the full recommended 
replacement dose is reached.  
  
1.4.1 Pregnancy  
 


71 
 
Pre-existing Hypothyroidism: LEVO-T dose requirements may increase during 
pregnancy. Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, 
at minimum, during each trimester of pregnancy.  In patients with primary 
hypothyroidism, maintain serum TSH in the trimester-specific reference range. For 
patients with serum TSH above the normal trimester- specific range, increase the dose 
of LEVO-T by 12.5 to 25 mcg/day and measure TSH every 4 weeks until a stable 
LEVO-T dose is reached and serum TSH is within the normal trimesterspecific range. 
Reduce LEVO-T dosage to pre-pregnancy levels immediately after delivery and  
measure serum TSH levels 4 to 8 weeks postpartum to ensure LEVO-T dose is 
appropriate.  
  
New Onset Hypothyroidism: Normalize thyroid function as rapidly as possible.   
 In 
patients with moderate to severe signs and symptoms of hypothyroidism, start LEVO-T 
at the full replacement dose (1.6 mcg per kg body weight per day).  In patients with mild 
hypothyroidism (TSH < 10 IU per liter) start LEVO-T at 1.0 mcg per kg body weight per 
day. Evaluate serum TSH every 4   
weeks and adjust LEVO-T dosage until a serum TSH is within the normal trimester 
specific range [see Use in Specific Populations (8.1)].  
  
1.4.2 TSH Suppression in Well-differentiated Thyroid Cancer  
Generally, TSH is suppressed to below 0.1 IU per liter, and this usually requires a LEVO-
T dose of greater than 2 mcg per kg per day. However, in patients with high-risk tumors, 
the target level for TSH suppression may be lower.  
  
5.2.2.1 2.4 Monitoring TSH and/or Thyroxine (T4) Levels  
Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical 
evaluation. Persistent clinical and laboratory evidence of hypothyroidism despite an 
apparent adequate replacement dose of LEVO-T may be evidence of inadequate 
absorption, poor compliance, drug interactions, or a combination of these factors.  
  
1.4.3 Adults  
In adult patients with primary hypothyroidism, monitor serum TSH levels after an 
interval of 6 to 8 weeks after any change in dose. In patients on a stable and 
appropriate replacement dose, evaluate clinical and biochemical response every 6 to 
12 months and whenever there is a change in the patient’s clinical status.  
  
1.4.4 Pediatrics  
In patients with congenital hypothyroidism, assess the adequacy of replacement 
therapy by measuring both serum TSH and total or free-T4. Monitor TSH and total or 
free-T4 in children as follows: 2 and 4 weeks after the initiation of treatment, 2 weeks 
after any change in dosage, and then every 3 to 12 months thereafter following dose 
stabilization until growth is completed. Poor compliance or abnormal values may 
necessitate more frequent monitoring. Perform routine clinical examination, including 
assessment of development, mental and physical growth, and bone maturation, at 
regular intervals.  
  
While the general aim of therapy is to normalize the serum TSH level, TSH may not normalize in 
some patients due to in utero hypothyroidism causing a resetting of pituitary-thyroid feedback. 
Failure of the serum T4 to increase into the upper half of the 


72 
 
normal range within 2 weeks of initiation of LEVO-T therapy and/or of the serum TSH to 
decrease below 20 IU per liter within 4 weeks may indicate the child is not receiving 
adequate therapy. Assess compliance, dose of medication administered, and method 
of administration prior to increasing the dose of LEVO-T [see Warnings and 
Precautions (5.1) and Use in Specific Populations (8.4)].  
  
1.4.5 Secondary and Tertiary Hypothyroidism  
Monitor serum free-T4 levels and maintain in the upper half of the normal range in 
these patients.  
  
1.5 3 DOSAGE FORMS AND STRENGTHS  
  
LEVO-T tablets are available as follows:  
  
Tablet 
Strength  
Tablet Color/Shape  Tablet Markings  
25 mcg  
Orange/Caplet  
“25” and “GG/331”  
50 mcg  
White/ Caplet  
“50” and “GG/332”  
75 mcg  
Violet/ Caplet  
“75” and “GG/333”  
88 mcg  
Olive Green/ Caplet  
“88” and “GG/334”  
100 mcg  
Yellow/ Caplet  
“100” and “GG/335”  
112 mcg  
Rose/ Caplet  
“112” and “GG/336”  
125 mcg  
Brown/ Caplet  
“125” and “GG/337”  
137 mcg  
Turquoise/ Caplet  
“137” and “GG/330”  
150 mcg  
Blue/ Caplet  
“150” and “GG/338”  
175 mcg  
Lilac/ Caplet  
“175” and “GG/339”  
200 mcg  
Pink/ Caplet  
“200” and “GG/340”  
300 mcg  
Green/ Caplet  
“300” and “GG/341”  
  
1.6 4 CONTRAINDICATIONS  
  
LEVO-T is contraindicated in patients with uncorrected adrenal insufficiency [see 
Warnings and Precautions (5.3)].  
  
1.7 5 WARNINGS AND PRECAUTIONS  
  
1.7.1 5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying 
Cardiovascular Disease  
Over-treatment with levothyroxine may cause an increase in heart rate, cardiac wall 
thickness, and cardiac contractility and may precipitate angina or arrhythmias, 
particularly in patients with cardiovascular disease and in elderly patients.  Initiate 
LEVO-T therapy in this population at lower doses than those recommended in younger 
individuals or in patients without cardiac disease [see Dosage and Administration (2.3), 
Use in Specific Populations (8.5)].  
  


73 
 
Monitor for cardiac arrhythmias during surgical procedures in patients with coronary 
artery disease receiving suppressive LEVO-T therapy. Monitor patients receiving 
concomitant  LEVOT and sympathomimetic agents for signs and symptoms of coronary 
insufficiency.  
  
If cardiac symptoms develop or worsen, reduce the LEVO-T dose or withhold for one 
week and restart at a lower dose.  
  
1.7.2 5.2 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. Use of oral thyroid hormone drug products is not 
recommended to treat myxedema coma. Administer thyroid hormone products 
formulated for intravenous administration to treat myxedema coma.  
  
5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency 
Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid  
hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute 
adrenal crisis in patients with adrenal insufficiency. Treat patients with adrenal 
insufficiency with replacement  glucocorticoids prior to initiating treatment with LEVO-T 
[see Contraindications (4)].  
  
5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism 
LEVO-T has a narrow therapeutic index. Over- or undertreatment with LEVO-T may  
 have negative effects on growth and development, cardiovascular function, bone 
metabolism, reproductive function, cognitive function, emotional state, gastrointestinal 
function, and glucose and lipid metabolism. Titrate the dose of LEVO-T carefully and 
monitor response to titration to avoid these effects [see Dosage and Administration 
(2.4)]. Monitor for the presence of drug or food interactions when using LEVO-T and 
adjust the dose as necessary [see Drug Interactions (7.9) and Clinical Pharmacology 
(12.3)].  
  
1.7.3 5.5 Worsening of Diabetic Control  
Addition of levothyroxine therapy in patients with diabetes mellitus may worsen 
glycemic control and result in increased antidiabetic agent or insulin requirements. 
Carefully monitor glycemic control after starting, changing, or discontinuing LEVO-T 
[see Drug Interactions (7.2)].  
  
5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-
Replacement Increased bone resorption and decreased bone mineral density may 
occur as a result of levothyroxine over-replacement, particularly in post-menopausal 
women. 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. Administer the 
minimum dose of LEVO-T that achieves the desired clinical and biochemical response 
to mitigate this risk.  
 
 


74 
 
1.8 ADVERSE REACTIONS  
  
Adverse reactions associated with LEVO-T therapy are primarily those of 
hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5), 
Overdosage (10)]. 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, muscle spasm  
• 
Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood 
pressure, heart failure, angina, myocardial infarction, cardiac arrest  
1.8.1 • 
  Respiratory: dyspnea  
• 
Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function 
tests  
• 
Dermatologic: hair loss, flushing, rash  
• 
Endocrine: decreased bone mineral density  
• 
Reproductive: menstrual irregularities, impaired fertility  
  
Seizures have been reported rarely with the institution of levothyroxine therapy.  
  
1.9 Adverse Reactions in Children  
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.  
  
1.10 Hypersensitivity Reactions  
Hypersensitivity reactions to inactive ingredients have occurred in patients treated with 
thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, 
angioedema, various gastrointestinal symptoms (abdominal pain, nausea, vomiting and 
diarrhea), fever, arthralgia, serum sickness, and wheezing. Hypersensitivity to 
levothyroxine itself is not known to occur.  
  
1.11 7 DRUG INTERACTIONS  
  
1.11.1 7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics  
Many drugs can exert effects on thyroid hormone pharmacokinetics and metabolism 
(e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue 
response) and may alter the therapeutic response to LEVO-T (see Tables 2-5 below).  
 
 
 
 


75 
 
Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism)  
Potential impact: Concurrent use may reduce the efficacy of LEVO-T by binding and 
delaying or preventing absorption, potentially resulting in hypothyroidism.  
Drug or Drug Class  
Effect  
Calcium Carbonate  
Calcium carbonate may form an insoluble chelate with  
Ferrous Sulfate  
levothyroxine, and ferrous sulfate likely forms a ferric- 
thyroxine complex. Administer LEVO-T at least 4 hours apart 
from these agents.  
Orlistat  
Monitor patients treated concomitantly with orlistat and LEVO-
T for changes in thyroid function.  
Bile Acid Sequestrants  
-Colesevelam  
-Cholestyramine  
-Colestipol  
Ion Exchange Resins  
-Kayexalate  
-Sevelamer  
Bile acid sequestrants and ion exchange resins are known to 
decrease levothyroxine absorption. Administer LEVO-T at 
least 4 hours prior to these drugs or monitor TSH levels.  
Other drugs:  
Gastric acidity is an essential requirement for adequate  
Proton Pump Inhibitors  
absorption of levothyroxine. Sucralfate, antacids and proton  
Sucralfate  
pump inhibitors may cause hypochlorhydria, affect intragastric 
Antacids  
pH, and reduce levothyroxine absorption. Monitor patients  
- Aluminum & Magnesium  
Hydroxides  
- Simethicone  
appropriately.  
  
Table 3. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport 
Without  
Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)  
Drug or Drug Class  
Effect  
Clofibrate  
Estrogen-containing oral 
contraceptives 
Estrogens (oral)  
Heroin / Methadone  
5-Fluorouracil  
Mitotane  
Tamoxifen  
These drugs may increase serum thyroxine-binding globulin 
(TBG) concentration.  
Androgens / Anabolic Steroids  
Asparaginase  
Glucocorticoids  
Slow-Release Nicotinic Acid  
These drugs may decrease serum TBG concentration.  
 


76 
 
Potential impact (below): Administration of these agents with LEVO-T results in an initial 
transient increase in FT4. Continued administration results in a decrease in serum T4 and 
normal FT4 and TSH concentrations.  
Salicylates (> 2 g/day)  
Salicylates inhibit binding of T4 and T3 to TBG and 
transthyretin. An initial increase in serum FT4 is followed by 
return of FT4 to normal levels with sustained therapeutic 
serum salicylate concentrations, although total T4 levels may 
decrease by as much as 30%.  
Other drugs:  
Carbamazepine  
Furosemide (> 80 mg IV)  
Heparin  
Hydantoins  
Non-Steroidal Anti-inflammatory  
Drugs  
-Fenamates  
 
These drugs may cause protein-binding site displacement.  
Furosemide has been shown to inhibit the protein binding of 
T4 to TBG and albumin, causing an increase free T4 fraction 
in serum. Furosemide competes for T4-binding sites on TBG, 
prealbumin, and albumin, so that a single high dose can 
acutely lower the total T4 level. Phenytoin and 
carbamazepine reduce serum protein binding of 
levothyroxine, and total and free T4 may be reduced by 20% 
to 40%, but most patients have normal serum TSH levels and 
are clinically euthyroid.  
Closely monitor thyroid hormone parameters.  
  
Table 4. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)  
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may 
cause increased hepatic degradation of levothyroxine, resulting in increased LEVO-T 
requirements.  
Drug or Drug Class  
Effect  
Phenobarbital 
Rifampin  
Phenobarbital has been shown to reduce the response to 
thyroxine. Phenobarbital increases L-thyroxine metabolism by 
inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) 
and leads to a lower T4 serum levels. Changes in thyroid 
status may occur if barbiturates are added or withdrawn from 
patients being treated for hypothyroidism. Rifampin has been 
shown to accelerate the metabolism of levothyroxine.  
  
Table 5. Drugs That May Decrease Conversion of T4 to T3  
Potential impact: 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.  
Drug or Drug Class  
Effect  
Beta-adrenergic antagonists  
(e.g., Propranolol > 160 mg/day)  
In patients treated with large doses of propranolol (> 160 
mg/day), T3 and T4 levels change, TSH levels remain normal, 
and patients are clinically euthyroid. Actions of particular beta-
adrenergic antagonists may be impaired when a hypothyroid 
patient is converted to the euthyroid state.  
 


77 
 
Glucocorticoids  
(e.g., Dexamethasone > 4 
mg/day)  
Short-term administration of large doses of glucocorticoids 
may decrease serum T3 concentrations by 30% with minimal 
change in serum T4 levels. However, long-term glucocorticoid 
therapy may result in slightly decreased T3 and T4 levels due 
to decreased TBG production (See above).  
Other drugs: 
Amiodarone  
Amiodarone inhibits peripheral conversion of levothyroxine 
(T4) to triiodothyronine (T3) and may cause isolated 
biochemical changes (increase in serum free-T4, and 
decreased or normal free-T3) in clinically euthyroid patients.  
  
7.2 Antidiabetic Therapy  
Addition of LEVO-T therapy in patients with diabetes mellitus may worsen glycemic 
control and result in increased antidiabetic agent or insulin requirements. Carefully 
monitor glycemic control, especially when thyroid therapy is started, changed, or 
discontinued [see Warnings and Precautions (5.5)].  
  
7.3 Oral Anticoagulants  
LEVO-T 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 LEVO-T dose is increased. Closely monitor coagulation tests to permit 
appropriate and timely dosage adjustments.  
  
7.4 Digitalis Glycosides  
LEVO-T may reduce the therapeutic effects of digitalis glycosides. Serum digitalis 
glycoside levels may decrease when a hypothyroid patient becomes euthyroid, 
necessitating an increase in the dose of digitalis glycosides.  
  
7.5 Antidepressant Therapy  
Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) 
antidepressants and LEVO-T 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 central nervous system 
stimulation. LEVO-T may accelerate the onset of action of tricyclics. Administration of 
sertraline in patients stabilized on LEVO-T may result in increased LEVO-T 
requirements.  
  
7.6 Ketamine  
Concurrent use of ketamine and LEVO-T may produce marked hypertension and 
tachycardia. Closely monitor blood pressure and heart rate in these patients.  
  
7.7 Sympathomimetics  
Concurrent use of sympathomimetics and LEVO-T 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.  
 
 


78 
 
7.8 Tyrosine-Kinase Inhibitors  
Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause 
hypothyroidism. Closely monitor TSH levels in such patients.  
  
7.9 Drug-Food Interactions  
Consumption of certain foods may affect LEVO-T absorption thereby necessitating 
adjustments in dosing [see Dosage and Administration (2.1)]. Soybean flour, 
cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of 
LEVO-T from the gastrointestinal tract. Grapefruit juice may delay the absorption of 
levothyroxine and reduce its bioavailability.  
  
7.10 Drug-Laboratory Test Interactions  
Consider changes in TBG concentration when interpreting T4 and T3 values. Measure 
and evaluate unbound (free) hormone and/or determine the free-T4 index (FT4I) in this 
circumstance. Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral 
contraceptives, and acute intermittent porphyria increase TBG concentration. 
Nephrosis, severe  
hypoproteinemia, severe liver disease, acromegaly, androgens, and corticosteroids 
decrease TBG concentration. Familial hyper- or hypo-thyroxine binding globulinemias 
have been described,  with the incidence of TBG deficiency approximating 1 in 9000.  
  
8 USE IN SPECIFIC POPULATIONS  
            8.1 Pregnancy Risk Summary  
  
Experience with levothyroxine use in pregnant women, including data from post-
marketing studies, have not reported increased rates of major birth defects or 
miscarriages [see Data]. There are risks to the mother and fetus associated with 
untreated hypothyroidism in pregnancy. Since TSH levels may increase during 
pregnancy, TSH should be monitored and LEVO-T dosage adjusted during pregnancy 
[see Clinical Considerations]. There are no animal studies conducted with levothyroxine 
during pregnancy. LEVO-T should not be discontinued during pregnancy and 
hypothyroidism diagnosed during pregnancy should be promptly treated.  
  
The estimated background risk of major birth defects and miscarriage for the indicated 
population is unknown. In the U.S. general population, the estimated background risk of 
major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 
15 to 20%, respectively.  
  
Clinical Considerations  
 
 
 
 
 
 
 
 
 


79 
 
Disease-Associated Maternal and/or Embryo/Fetal Risk  
Maternal hypothyroidism during pregnancy is associated with a higher rate of 
complications, including spontaneous abortion, gestational hypertension, pre-
eclampsia, stillbirth, and premature delivery. Untreated maternal hypothyroidism may 
have an adverse effect on fetal neurocognitive development.  
  
Dose Adjustments During Pregnancy and the Postpartum Period  
Pregnancy may increase LEVO-T requirements. Serum TSH levels should be 
monitored and the LEVO-T dosage adjusted during pregnancy. Since postpartum TSH 
levels are similar to preconception values, the LEVO-T dosage should return to the pre-
pregnancy dose immediately after delivery [see Dosage and Administration (2.3)].  
  
Data  
  
Human Data  
Levothyroxine is approved for use as a replacement therapy for hypothyroidism. There 
is a long experience of levothyroxine use in pregnant women, including data from post-
marketing studies that have not reported increased rates of fetal malformations, 
miscarriages or other adverse maternal or fetal outcomes associated with levothyroxine 
use in pregnant women.  
  
8.2 Lactation  
Risk Summary  
  
Limited published studies report that levothyroxine is present in human milk. However, 
there is insufficient information to determine the effects of Levothyroxine on the 
breastfed infant and no available information on the effects of levothyroxine on milk 
production. Adequate levothyroxine treatment during lactation may normalize milk 
production in hypothyroid lactating mothers. The developmental and health benefits of 
breastfeeding should be considered along with the mother’s clinical need for LEVO-T 
and any potential adverse effects on the breastfed infant from LEVO-T or from the 
underlying maternal condition.  
  
8.4 Pediatric Use  
The initial dose of LEVO-T varies with age and body weight. Dosing adjustments are 
based on an assessment of the individual patient's clinical and laboratory parameters 
[see Dosage and Administration (2.3, 2.4)].  
  
In children in whom a diagnosis of permanent hypothyroidism has not been 
established, discontinue LEVO-T administration for a trial period, but only after the child 
is at least 3 years of age. Obtain serum T4 and TSH levels at the end of the trial period, 
and use laboratory test results and clinical assessment to guide diagnosis and 
treatment, if warranted.  
  
Congenital Hypothyroidism [See Dosage and Administration (2.3, 2.4)]  
 
 


80 
 
Rapid restoration of normal serum T4 concentrations is essential for preventing the 
adverse effects of congenital hypothyroidism on intellectual development as well as on 
overall physical growth and maturation. Therefore, initiate LEVO-T therapy immediately 
upon diagnosis. Levothyroxine is generally continued for life in these patients.  
  
Closely monitor infants during the first 2 weeks of LEVO-T therapy for cardiac overload, 
arrhythmias, and aspiration from avid suckling.  
  
Closely monitor patients to avoid undertreatment or overtreatment. Undertreatment 
may have deleterious effects on intellectual development and linear growth. 
Overtreatment is associated with craniosynostosis in infants, may adversely affect the 
tempo of brain maturation, and may accelerate the bone age and result in premature 
epiphyseal closure and compromised adult stature.  
  
Acquired Hypothyroidism in Pediatric Patients  
Closely monitor patients to avoid undertreatment and overtreatment. Undertreatment 
may result in poor school performance due to impaired concentration and slowed 
mentation and in reduced adult height. Overtreatment may accelerate the bone age 
and result in premature epiphyseal closure and compromised adult stature.  
  
Treated children may manifest a period of catch-up growth, which may be adequate in 
some cases to normalize adult height. In children with severe or prolonged 
hypothyroidism, catch-up growth may not be adequate to normalize adult height.  
  
8.5 Geriatric Use  
Because of the increased prevalence of cardiovascular disease among the elderly, 
initiate LEVOT at less than the full replacement dose [see Warnings and Precautions 
(5.1) and Dosage and  
Administration (2.3)]. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is 
the most common of the arrhythmias observed with levothyroxine overtreatment in the 
elderly.  
  
10 OVERDOSAGE  
  
The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings 
and  
Precautions (5) and Adverse Reactions (6)]. In addition, confusion and disorientation 
may occur. Cerebral embolism, shock, coma, and death have been reported. Seizures 
occurred in a 3-year old child ingesting 3.6 mg of levothyroxine. Symptoms may not 
necessarily be evident or may not appear until several days after ingestion of 
levothyroxine sodium.  
  
Reduce the LEVO-T dose or discontinue temporarily if signs or symptoms of 
overdosage occur. Initiate appropriate supportive treatment as dictated by the patient’s 
medical status.  
  
For current information on the management of poisoning or overdosage, contact the 
National Poison Control Center at 1-800-222-1222 or www.poison.org.  


81 
 
11 DESCRIPTION  
  
LEVO-T (levothyroxine sodium tablets, USP) contain synthetic crystalline L-3,3',5,5' 
tetraiodothyronine sodium salt [levothyroxine (T4) sodium]. Synthetic T4 is chemically 
identical to that produced in the human thyroid gland. Levothyroxine (T4) sodium has 
an empirical formula of C15H10I4NNaO4•xH2O (where x = 5), molecular weight of 798.86 
g/mol (anhydrous), and structural formula as shown:  
  
LEVO-T tablets for oral administration are supplied in the following strengths: 25 mcg, 
50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 
200 mcg, and  
300 mcg. Each LEVO-T tablet contains the inactive ingredients Magnesium Stearate, 
NF; Microcrystalline Cellulose, NF; Colloidal Silicone Dioxide, NF; and Sodium Starch 
Glycolate, NF. Each tablet strength meets USP Dissolution Test 2. Table 6 provides 
a listing of the color additives by tablet strength:  
  
Table 6. LEVO-T Tablets Color Additives  
Strength 
(mcg)  
Color additive(s)  
25  
FD&C Yellow No. 6 Aluminum Lake   
50  
None  
75  
FD&C Blue No. 2 Aluminum Lake, D&C Red No. 27 Aluminum Lake  
88  
FD&C Blue No. 1 Aluminum Lake, D&C Yellow No. 10 Aluminum Lake, D&C Red 
No. 30 Aluminum Lake  
100  
D&C Yellow No. 10 Aluminum Lake, D&C Red Lake Blend (D&C Red No. 27 Lake 
and D&C Red No. 30 Lake)   
112  
D&C Red No. 27 Aluminum Lake, D&C Red No. 30 Aluminum Lake  
125  
FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C 
Blue No. 1 Aluminum Lake  
137  
FD&C Blue No. 1 Aluminum Lake  
150  
FD&C Blue No. 2 Aluminum Lake  
175  
D&C Red No. 27 Aluminum Lake, D&C Red No. 30 Aluminum Lake, FD&C Blue 
No. 1 Aluminum Lake  
200  
D&C Yellow No. 10 Aluminum Lake, D&C Red No. 27 Aluminum Lake  
 


82 
 
 
300  
D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake, FD&C 
Blue No. 1 Aluminum Lake  
  
12 CLINICAL PHARMACOLOGY  
  
12.1 Mechanism of Action  
Thyroid hormones exert their physiologic actions through control of DNA transcription 
and protein synthesis. Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell 
nucleus and  bind to thyroid receptor proteins attached to DNA. This hormone nuclear 
receptor complex activates gene transcription and synthesis of messenger RNA and 
cytoplasmic proteins.  
  
The physiological actions of thyroid hormones are produced predominantly by T3, the 
majority of which (approximately 80%) is derived from T4 by deiodination in peripheral 
tissues.  
  
12.2 Pharmacodynamics  
Oral levothyroxine sodium is a synthetic T4 hormone that exerts the same physiologic 
effect as endogenous T4, thereby maintaining normal T4 levels when a deficiency is 
present.  
  
12.3 Pharmacokinetics  
  
Absorption  
Absorption of orally administered T4 from the gastrointestinal tract ranges from 40% to 
80%. The majority of the LEVO-T dose is absorbed from the jejunum and upper ileum. 
The relative bioavailability of LEVO-T tablets, compared to an equal nominal dose of 
oral levothyroxine sodium solution, is approximately 99%. T4 absorption is increased by 
fasting, and decreased in malabsorption syndromes and by certain foods such as 
soybeans. Dietary fiber decreases bioavailability of T4. Absorption may also decrease 
with age. In addition, many drugs and foods affect T4 absorption [see Drug Interactions 
(7)].  
  
Distribution  
Circulating thyroid hormones are greater than 99% bound to plasma proteins, including 
thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin 
(TBA), whose capacities and affinities vary for each hormone. The higher affinity of 
both TBG and TBPA for T4 partially explains the higher serum levels, slower metabolic 
clearance, and longer half-life of T4 compared to T3. Protein-bound thyroid hormones 
exist in reverse equilibrium with small amounts of free hormone. Only unbound 
hormone is metabolically active. Many drugs and physiologic conditions affect the 
binding of thyroid hormones to serum proteins [see Drug Interactions (7)]. Thyroid 
hormones do not readily cross the placental barrier [see Use in Specific Populations 
(8.1)].  
  


83 
 
1.11.2 Elimination 
Metabolism  
T4 is slowly eliminated (see Table 7). The major pathway of thyroid hormone 
metabolism is through sequential deiodination. Approximately 80% of circulating T3 is 
derived from peripheral T4 by monodeiodination. The liver is the major site of 
degradation for both T4 and T3, with T4 deiodination also occurring at a number of 
additional sites, including the kidney and other tissues. Approximately 80% of the daily 
dose of T4 is deiodinated to yield equal amounts of T3 and reverse T3 (rT3). T3 and 
rT3 are further deiodinated to diiodothyronine. Thyroid hormones are also metabolized 
via conjugation with glucuronides and sulfates and excreted directly into the bile and 
gut where they undergo enterohepatic recirculation.  
  
Excretion  
Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated 
hormone reaches the colon unchanged and is eliminated in the feces. Approximately 
20% of T4 is eliminated in the stool. Urinary excretion of T4 decreases with age.  
  
Table 7. Pharmacokinetic Parameters of Thyroid Hormones in Euthyroid Patients  
Hormone  
Ratio in Thyroglobulin  Biologic 
Potency  
t1/2 (days) Protein Binding (%)a   
Levothyroxine (T4)  
10 - 20  
1  
6-7b   
99.96  
Liothyronine (T3)  
1  
4  
≤ 2   
99.5  
a. 
Includes TBG, TBPA, and TBA  
b. 
3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism  
  
13 NONCLINICAL TOXICOLOGY  
  
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility  
Standard animal studies have not been performed to evaluate the carcinogenic 
potential, mutagenic potential or effects on fertility of levothyroxine.  
  
16 HOW SUPPLIED/STORAGE AND HANDLING  
  
LEVO-T (levothyroxine sodium, USP) tablets are supplied as follows:  
Strength 
(mcg)  
Color/Shape  
Tablet Markings  
NDC# for  
bottles of 90  
NDC # for 
bottles of 1000 
25  
Orange/Caplet  
“25” and “GG/331”  
55466-104-11  
55466-104-19 
50  
White/ Caplet  
“50” and “GG/332”  
55466-105-11  
55466-105-19 
 
 
 
 


84 
 
75  
Violet/ Caplet  
“75” and  “GG/333”  55466-106-11  
55466-106-19 
88  
Olive 
Green/ 
Caplet  
“88” and  ‘GG/334”  
55466-107-11  
-  
100  
Yellow/ Caplet  
“100” and “GG/335” 55466-108-11  
55466-108-19 
112  
Rose/ Caplet  
“112” and “GG/336” 55466-109-11  
-  
125  Brown/ Caplet  
“125” and “GG/337” 
55466-110-11  55466-110-19 
137  Turquoise/ Caplet  “137” and “GG/330” 
55466-111-11  
-  
150  Blue/ Caplet  
“150” and “GG/338” 
55466-112-11  
-  
175  Lilac/ Caplet  
“175” and “GG/339” 
55466-113-11  
-  
200  Pink/ Caplet  
“200” and “GG/340” 
55466-114-11  
-  
300  Green/ Caplet  
“300” and “GG/341” 
55466-115-11  
-  
  
Storage Conditions  
Store at 25°C (77°F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP 
Controlled Room Temperature]. LEVO-T tablets should be protected from light and 
moisture.  
  
17 PATIENT COUNSELING INFORMATION Inform the patient of the following 
information to aid in the safe and effective use of  
  
LEVO-T:  
  
Dosing and Administration  
  
• 
Instruct patients that LEVO-T should be taken with a full glass of water since the 
tablet may rapidly disintegrate.  
• 
Instruct patients to take LEVO-T only as directed by their healthcare provider.  
• 
Instruct patients to take LEVO-T as a single dose, preferably on an empty stomach, 
one-half to one hour before breakfast.  
• 
Inform patients that agents such as iron and calcium supplements and antacids can 
decrease the absorption of levothyroxine. Instruct patients not to take LEVO-T 
tablets within 4 hours of these agents.  
• 
Instruct patients to notify their healthcare provider if they are pregnant or 
breastfeeding or are thinking of becoming pregnant while taking LEVO-T.  
  
Important Information  
  


85 
 
• 
Inform patients that it may take several weeks before they notice an improvement in 
symptoms.  
• 
Inform patients that the levothyroxine in LEVO-T is intended to replace a hormone 
that is normally produced by the thyroid gland. Generally, replacement therapy is to 
be taken for life.  
• 
Inform patients that LEVO-T should not be used as a primary or adjunctive therapy 
in a weight control program.  
• 
Instruct patients to notify their healthcare provider if they are taking any other 
medications, including prescription and over-the-counter preparations.  
• 
Instruct patients to notify their physician of any other medical conditions they may 
have, particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary 
gland problems, as the dose of medications used to control these other conditions 
may need to be adjusted while they are taking LEVO-T. If they have diabetes, 
instruct patients to monitor their blood and/or urinary glucose levels as directed by 
their physician and immediately report any changes to their physician. If patients 
are taking anticoagulants, their clotting status should be checked frequently.  
• 
Instruct patients to notify their physician or dentist that they are taking LEVO-T prior 
to any surgery.  
  
Adverse Reactions  
  
• 
Instruct patients to notify their healthcare provider if they experience any of the 
following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, 
leg cramps, headache, nervousness, irritability, sleeplessness, tremors, change in 
appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat 
intolerance, fever, changes in menstrual periods, hives or skin rash, or any other 
unusual medical event.  
• 
Inform patients that partial hair loss may occur rarely during the first few months of 
LEVO-T therapy, but this is usually temporary.  
  
  
Manufactured and Distributed by:    
Neolpharma, Inc.    
Caguas, Puerto Rico  00725    
  
December 2017    
  
PP10402    
  
IGH  
 
 
 
 
 
 


86 
 
Appendix C 
LEVOTHYROXINE SODIUM- levothyroxine sodium tablet  Mylan 
Pharmaceuticals Inc. 
---------- 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use LEVOTHYROXINE SODIUM TABLETS safely 
and effectively. See full prescribing information for LEVOTHYROXINE SODIUM TABLETS. 
  
LEVOTHYROXINE SODIUM tablets, for oral use  
Initial U.S. Approval: 2002 
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS 
See full prescribing information for complete boxed warning 
• 
• 
Thyroid hormones, including levothyroxine sodium tablets should not be used for the treatment of obesity or for 
weight loss. 
Doses beyond the range of daily hormonal requirements may produce serious or even life threatening 
manifestations of toxicity (6, 10). 
 
Levothyroxine sodium tablets are levothyroxine sodium (T4) indicated for: 
• Hypothyroidism: As replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary 
(hypothalamic) congenital or acquired hypothyroidism. (1) 
• Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression: As an adjunct to surgery 
and radioiodine therapy in the management of thyrotropin-dependent well-differentiated thyroid 
cancer. (1) Limitations of Use: 
- 
Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in 
iodine-sufficient patients. - 
Not indicated for treatment of hypothyroidism during the 
recovery phase of subacute thyroiditis. 
 
• Administer once daily, preferably on an empty stomach, one-half to one hour before breakfast. (2.1) 
• Administer at least 4 hours before or after drugs that are known to interfere with absorption. (2.1) 
• Evaluate the need for dose adjustments when regularly administering within one hour of certain 
foods that may affect absorption. (2.1) 
• Starting dose depends on a variety of factors, including age, body weight, cardiovascular status, 
and concomitant medications. Peak therapeutic effect may not be attained for 4-6 weeks. (2.2) 
• See full prescribing information for dosing in specific patient populations. (2.3) 
• Adequacy of therapy determined with periodic monitoring of TSH and/or T4 as well as clinical status. 
(2.4) 
 
 
 
 
 
 


87 
 
  
 
• Cardiac adverse reactions in the elderly and in patients with underlying cardiovascular disease: Initiate 
levothyroxine sodium tablets at less than the full replacement dose because of the increased risk of 
cardiac adverse reactions, including atrial fibrillation. (2.3, 5.1, 8.5) 
• Myxedema coma: Do not use oral thyroid hormone drug products to treat myxedema coma. (5.2) 
• Acute adrenal crisis in patients with concomitant adrenal insufficiency: Treat with replacement 
glucocorticoids prior to initiation of levothyroxine sodium tablets treatment. (5.3) 
• Prevention of hyperthyroidism or incomplete treatment of hypothyroidism: Proper dose titration and 
careful monitoring is critical to prevent the persistence of hypothyroidism or the development of 
hyperthyroidism. (5.4) 
• Worsening of diabetic control: Therapy in patients with diabetes mellitus may worsen glycemic control 
and result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control 
after starting, changing, or discontinuing thyroid hormone therapy. (5.5) 
• Decreased bone mineral density associated with thyroid hormone over-replacement: Over-replacement 
can increase bone resorption and decrease bone mineral density. Give the lowest effective dose. 
(5.6) 
 
Adverse reactions associated with levothyroxine sodium tablets therapy are primarily those of 
hyperthyroidism due to therapeutic overdosage: arrhythmias, myocardial infarction, dyspnea, muscle 
spasm, headache, nervousness, irritability, insomnia, tremors, muscle weakness, increased appetite, 
weight loss, diarrhea, heat intolerance, menstrual irregularities, and skin rash. (6) 
To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-8774-
INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 
 
See full prescribing information for drugs that affect thyroid hormone pharmacokinetics and 
metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue 
response) and may alter the therapeutic response to levothyroxine sodium tablets. (7) 
 
Pregnancy may require the use of higher doses of levothyroxine sodium tablets. (2.3, 8.1) 
See 17 for PATIENT COUNSELING INFORMATION. 
Revised: 10/2017 
 
FULL PRESCRIBING INFORMATION: CONTENTS* 
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS 
1 INDICATIONS AND USAGE 
2 DOSAGE AND ADMINISTRATION 
2.1 General Administration Information 
2.2 General Principles of Dosing 
 
 
  
 
 
 
   
 
 
 


88 
 
2.3 Dosing in Specific Patient Populations 
2.4 Monitoring TSH and/or Thyroxine (T4) Levels 
3 DOSAGE FORMS AND STRENGTHS 
4 CONTRAINDICATIONS 
5 WARNINGS AND PRECAUTIONS 
5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying 
CardiovascularDisease 
5.2 Myxedema Coma 
5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency 
5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism 
5.5 Worsening of Diabetic Control 
5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-Replacement 
6 ADVERSE REACTIONS 
7 DRUG INTERACTIONS 
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics 
7.2 Antidiabetic Therapy 
7.3 Oral Anticoagulants 
7.4 Digitalis Glycosides 
7.5 Antidepressant Therapy 
7.6 Ketamine 
7.7 Sympathomimetics 
7.8 Tyrosine-Kinase Inhibitors 
7.9 Drug-Food Interactions 
7.10 Drug-Laboratory Test Interactions 
8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
8.2 Lactation 
8.4 
Pediatric Use 
8.5 
Geriatric Use10 OVERDOSAGE 
11 DESCRIPTION 
12 CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
12.2 
Pharmacodynamics 
12.3 
Pharmacokinetics 
13 NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility16 HOW SUPPLIED/STORAGE 
AND HANDLING 17 PATIENT COUNSELING INFORMATION 
* Sections or subsections omitted from the full prescribing information are not listed. 
 
 


89 
 
FULL PRESCRIBING INFORMATION 
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS 
Thyroid hormones, including levothyroxine sodium tablets, either alone or with other 
therapeutic agents, should not be used for the treatment of obesity or for weight loss. 
In euthyroid patients, doses within the range of daily hormonal requirements are ineffective 
for weight reduction. 
Larger doses may produce serious or even life threatening manifestations of toxicity, 
particularly when given in association with sympathomimetic amines such as those used for 
their anorectic effects [see Adverse Reactions (6), Drug Interactions (7.7), and Overdosage 
(10)]. 
1 INDICATIONS AND USAGE 
Hypothyroidism: Levothyroxine sodium tablets are indicated as a replacement therapy in 
primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired 
hypothyroidism. 
Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression: Levothyroxine sodium 
tablets are indicated as an adjunct to surgery and radioiodine therapy in the management of 
thyrotropindependent well-differentiated thyroid cancer. 
Limitations of Use: 
• Levothyroxine sodium tablets are not indicated for suppression of benign thyroid nodules 
and nontoxic diffuse goiter in iodine-sufficient patients as there are no clinical benefits and 
overtreatment with levothyroxine sodium tablets may induce hyperthyroidism [see 
Warnings and Precautions (5.4)]. 
• Levothyroxine sodium tablets are not indicated for treatment of hypothyroidism during the 
recovery phase of subacute thyroiditis. 
2 DOSAGE AND ADMINISTRATION 
2.1 General Administration Information 
Administer levothyroxine sodium tablets as a single daily dose, on an empty stomach, one-half 
to one hour before breakfast. 
Administer levothyroxine sodium tablets at least 4 hours before or after drugs known to interfere 
with levothyroxine sodium tablets absorption [see Drug Interactions (7.1)]. 
Evaluate the need for dose adjustments when regularly administering within one hour of 
certain foods that may affect levothyroxine sodium tablets absorption [see Drug Interactions 
(7.9)and Clinical Pharmacology (12.3)]. 
Administer levothyroxine sodium tablets to infants and children who cannot swallow intact 
tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 to 10 
mL or 1 to 2 teaspoons) of water and immediately administering the suspension by spoon or 
dropper. Do not store the suspension. Do not administer in foods that decrease absorption of 
levothyroxine sodium tablets, such as soybean-based infant formula [see Drug Interactions (7.9)]. 
2.2 General Principles of Dosing 


90 
 
The dose of levothyroxine sodium tablets for hypothyroidism or pituitary TSH suppression depends on a 
variety of factors including: the patient's age, body weight, cardiovascular status, concomitant medical 
conditions (including pregnancy), concomitant medications, co-administered food and the specific 
nature of the condition being treated [see Dosage and Administration (2.3), Warnings and Precautions 
(5), and Drug Interactions (7)]. Dosing must be individualized to account for these factors and dose 
adjustments made based on periodic assessment of the patient's clinical response and laboratory 
parameters [see Dosage and Administration (2.4)]. 
The peak therapeutic effect of a given dose of levothyroxine sodium tablets may not be attained for 4 to 
6 weeks. 
2.3 Dosing in Specific Patient Populations 
2 PRIMARY HYPOTHYROIDISM IN ADULTS AND IN ADOLESCENTS IN WHOM GROWTH AND 
PUBERTY ARE COMPLETE 
Start levothyroxine sodium tablets at the full replacement dose in otherwise healthy, non-elderly 
individuals who have been hypothyroid for only a short time (such as a few months). The average full 
replacement dose of levothyroxine sodium tablets is approximately 1.6 mcg per kg per day (for 
example: 100 to 125 mcg per day for a 70 kg adult). 
Adjust the dose by 12.5 to 25 mcg increments every 4 to 6 weeks until the patient is clinically euthyroid 
and the serum TSH returns to normal. Doses greater than 200 mcg per day are seldom required. An 
inadequate response to daily doses of greater than 300 mcg per day is rare and may indicate poor 
compliance, malabsorption, drug interactions, or a combination of these factors. 
For elderly patients or patients with underlying cardiac disease, start with a dose of 12.5 to 25 mcg per 
day. Increase the dose every 6 to 8 weeks, as needed until the patient is clinically euthyroid and the 
serum TSH returns to normal. The full replacement dose of levothyroxine sodium tablets may be less 
than 1 mcg per kg per day in elderly patients. 
In patients with severe longstanding hypothyroidism, start with a dose of 12.5 to 25 mcg per day. 
Adjust the dose in 12.5 to 25 mcg increments every 2 to 4 weeks until the patient is clinically euthyroid 
and the serum TSH level is normalized. 
3 SECONDARY OR TERTIARY HYPOTHYROIDISM 
Start levothyroxine sodium tablets at the full replacement dose in otherwise healthy, non-elderly 
individuals. Start with a lower dose in elderly patients, patients with underlying cardiovascular disease 
or patients with severe longstanding hypothyroidism as described above. Serum TSH is not a reliable 
measure of levothyroxine sodium tablets dose adequacy in patients with secondary or tertiary 
hypothyroidism and should not be used to monitor therapy. Use the serum free-T4 level to monitor 
adequacy of therapy in this patient population. Titrate levothyroxine sodium tablets dosing per above 
instructions until the patient is clinically euthyroid and the serum free-T4 level is restored to the upper 
half of the normal range. 
4 PEDIATRIC DOSAGE-CONGENITAL OR ACQUIRED HYPOTHYROIDISM 
The recommended daily dose of levothyroxine sodium tablets in pediatric patients 
with hypothyroidism is based on body weight and changes with age as described in 
Table 1. Start 


91 
 
 
levothyroxine sodium tablets at the full daily dose in most pediatric patients. Start at a lower 
starting dose in newborns (0-3 months) at risk for cardiac failure and in children at risk for 
hyperactivity (see below). Monitor for clinical and laboratory response [see Dosage and 
Administration (2.4)]. 
5 TABLE 1. LEVOTHYROXINE SODIUM TABLETS DOSING 
GUIDELINES FOR PEDIATRIC HYPOTHYROIDISM 
* The dose should be adjusted based on clinical response and laboratory parameters [see Dosage and 
Administration (2.4) and Use in Specific Populations (8.4)]. 
5.1 Newborns (0-3 months) at Risk for Cardiac Failure 
Consider a lower starting dose in newborns at risk for cardiac failure. Increase the dose every 4 
to 6 
weeks as needed based on clinical and laboratory response. 
5.2 Children at Risk for Hyperactivity 
To minimize the risk of hyperactivity in children, start at one-fourth the recommended full 
replacement dose, and increase on a weekly basis by one-fourth the full recommended 
replacement dose until the full recommended replacement dose is reached. 
5.3 Pregnancy 
Pre-Existing Hypothyroidism 
Levothyroxine sodium tablets dose requirements may increase during pregnancy. Measure 
serum TSH and free-T4 as soon as pregnancy is confirmed and, at minimum, during each 
trimester of pregnancy. In patients with primary hypothyroidism, maintain serum TSH in the 
trimester-specific reference range. For patients with serum TSH above the normal trimester-
specific range, increase the dose of levothyroxine sodium tablets by 12.5 to 25 mcg/day and 
measure TSH every 4 weeks until a stable levothyroxine sodium tablets dose is reached and 
serum TSH is within the normal trimester-specific range. Reduce levothyroxine sodium tablets 
dosage to pre-pregnancy levels immediately after delivery and measure serum TSH levels 4 to 
8 weeks postpartum to ensure levothyroxine sodium tablets dose is appropriate. 
New Onset Hypothyroidism 
 
 
0-3 
 
 
 
3-6 
 
 
 
 
 
6-8 
 
1-5 
 
5-6 
 
 
 
4-5 
 
 
2-3 
 
 
 
 
 


92 
 
Normalize thyroid function as rapidly as possible. In patients with moderate to severe signs 
and symptoms of hypothyroidism, start levothyroxine sodium tablets at the full replacement 
dose (1.6 mcg per kg body weight per day). In patients with mild hypothyroidism (TSH < 10 
IU per liter) start levothyroxine sodium tablets at 1.0 mcg per kg body weight per day. 
Evaluate serum TSH every 4 weeks and adjust levothyroxine sodium tablets dosage until a 
serum TSH is within the normal trimester specific range [see Use in Specific Populations (8.1)]. 
5.4 TSH Suppression in Well-Differentiated Thyroid Cancer 
Generally, TSH is suppressed to below 0.1 IU per liter, and this usually requires a levothyroxine 
sodium tablets dose of greater than 2 mcg per kg per day. However, in patients with high-risk 
tumors, the target level for TSH suppression may be lower. 
2.4 Monitoring TSH and/or Thyroxine (T4) Levels 
Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical 
evaluation. Persistent clinical and laboratory evidence of hypothyroidism despite an apparent 
adequate replacement dose of levothyroxine sodium tablets may be evidence of inadequate 
absorption, poor compliance, drug interactions, or a combination of these factors. 
5.5 Adults 
In adult patients with primary hypothyroidism, monitor serum TSH levels after an interval of 6 
to 8 weeks after any change in dose. In patients on a stable and appropriate replacement 
dose, evaluate clinical and biochemical response every 6 to 12 months and whenever there is 
a change in the patient’s clinical status. 
5.6 Pediatrics 
In patients with congenital hypothyroidism, assess the adequacy of replacement therapy by 
measuring both serum TSH and total or free-T4. Monitor TSH and total or free-T4 in children as 
follows: 2 and 4 weeks after the initiation of treatment, 2 weeks after any change in dosage, and 
then every 3 to 12 months thereafter following dose stabilization until growth is completed. Poor 
compliance or abnormal values may necessitate more frequent monitoring. Perform routine 
clinical examination, including assessment of development, mental and physical growth, and 
bone maturation, at regular intervals. 
While the general aim of therapy is to normalize the serum TSH level, TSH may not normalize 
in some patients due to in utero hypothyroidism causing a resetting of pituitary-thyroid feedback. 
Failure of the serum T4 to increase into the upper half of the normal range within 2 weeks of 
initiation of 
levothyroxine sodium tablets therapy and/or of the serum TSH to decrease below 20 IU per liter 
within 
4 weeks may indicate the child is not receiving adequate therapy. Assess compliance, 
dose of medication administered, and method of administration prior to increasing the dose 
of levothyroxine sodium tablets [see Warnings and Precautions (5.1)and Use in Specific 
Populations (8.4)]. 
5.7 Secondary and Tertiary Hypothyroidism 
Monitor serum free-T4 levels and maintain in the upper half of the normal range in these 
patients. 


93 
 
3 DOSAGE FORMS AND STRENGTHS 
Levothyroxine Sodium Tablets, USP are available containing 25 mcg, 50 mcg, 75 mcg, 88 mcg, 
100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 mcg or 300 mcg of 
levothyroxine sodium, USP. 
• The 25 mcg tablets are orange, capsule-shaped, scored tablets debossed with L to the left 
of the score and 4 to the right of the score on one side of the tablet and M on the other side. 
• The 50 mcg tablets are white, capsule-shaped, scored tablets debossed with L to the left of 
the score and 5 to the right of the score on one side of the tablet and M on the other side. 
• The 75 mcg tablets are violet, capsule-shaped, scored tablets debossed with L to the left of 
the score and 6 to the right of the score on one side of the tablet and M on the other side. 
• The 88 mcg tablets are olive, capsule-shaped, scored tablets debossed with L to the left of 
the score and 7 to the right of the score on one side of the tablet and M on the other side. 
• The 100 mcg tablets are yellow, capsule-shaped, scored tablets debossed with L to the left 
of the score and 8 to the right of the score on one side of the tablet and M on the other side. 
• The 112 mcg tablets are rose, capsule-shaped, scored tablets debossed with L to the left 
of the score and 9 to the right of the score on one side of the tablet and M on the other side. 
• The 125 mcg tablets are gray, capsule-shaped, scored tablets debossed with L to the left 
of the score and 10 to the right of the score on one side of the tablet and M on the other 
side. 
• The 137 mcg tablets are turquoise, capsule-shaped, scored tablets debossed with L to the 
left of the score and 15 to the right of the score on one side of the tablet and M on the other 
side. 
• The 150 mcg tablets are blue, capsule-shaped, scored tablets debossed with L to the left 
of the score and 11 to the right of the score on one side of the tablet and M on the other 
side. 
• The 175 mcg tablets are lilac, capsule-shaped, scored tablets debossed with L to the left of 
the score and 12 to the right of the score on one side of the tablet and M on the other side. 
• The 200 mcg tablets are pink, capsule-shaped, scored tablets debossed with L to the left 
of the score and 13 to the right of the score on one side of the tablet and M on the other 
side. 
• The 300 mcg tablets are green, capsule-shaped, scored tablets debossed with L to the left 
of the score and 14 to the right of the score on one side of the tablet and M on the other 
side. 
4 CONTRAINDICATIONS 
Levothyroxine sodium tablets are contraindicated in patients with uncorrected adrenal 
insufficiency [see Warnings and Precautions (5.3)]. 
5 WARNINGS AND PRECAUTIONS 


94 
 
5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying 
CardiovascularDisease 
Over-treatment with levothyroxine may cause an increase in heart rate, cardiac wall thickness, and 
cardiac contractility and may precipitate angina or arrhythmias, particularly in patients with 
cardiovascular disease and in elderly patients. Initiate levothyroxine sodium tablets therapy in this 
population at lower doses than those recommended in younger individuals or in patients without 
cardiac disease [see Dosage and Administration (2.3), and Use in Specific Populations (8.5)]. 
Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease 
receiving suppressive levothyroxine sodium tablets therapy. Monitor patients receiving concomitant 
levothyroxine sodium tablets and sympathomimetic agents for signs and symptoms of coronary 
insufficiency. 
If cardiac symptoms develop or worsen, reduce the levothyroxine sodium tablets dose or withhold for 
one week and restart at a lower dose. 
5.2 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. Use of oral thyroid hormone drug products is not recommended to treat 
myxedema coma. Administer thyroid hormone products formulated for intravenous administration to 
treat myxedema coma. 
5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency 
Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid hormone 
therapy prior to initiating glucocorticoid therapy may precipitate an acute adrenal crisis in patients with 
adrenal insufficiency. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to 
initiating treatment with levothyroxine sodium tablets [see Contraindications (4)]. 
5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism 
Levothyroxine sodium tablets have a narrow therapeutic index. Over- or undertreatment with 
levothyroxine sodium tablets may have negative effects on growth and development, cardiovascular 
function, bone metabolism, reproductive function, cognitive function, emotional state, 
gastrointestinal function, and glucose and lipid metabolism. Titrate the dose of levothyroxine sodium 
tablets carefully and monitor response to titration to avoid these effects [see Dosage and 
Administration (2.4)]. Monitor for the presence of drug or food interactions when using levothyroxine 
sodium tablets and adjust the dose as necessary [see Drug Interactions (7.9)and Clinical 
Pharmacology (12.3)]. 
5.5 Worsening of Diabetic Control 
Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and 
result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after 
starting, changing, or discontinuing levothyroxine sodium tablets [see Drug Interactions (7.2)]. 
5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-Replacement 
Increased bone resorption and decreased bone mineral density may occur as a result of levothyroxine 
over-replacement, particularly in post-menopausal women. The increased bone resorption may be 
associated with increased serum levels and urinary excretion of calcium and phosphorous, 


95 
 
elevations in bone alkaline phosphatase, and suppressed serum parathyroid hormone levels. 
Administer the minimum dose of levothyroxine sodium tablets that achieves the desired clinical 
and biochemical response to mitigate this risk. 
6 ADVERSE REACTIONS 
Adverse reactions associated with levothyroxine sodium tablets therapy are primarily those of 
hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5), and Overdosage 
(10)]. 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, muscle spasm 
• Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, 
heart failure, angina, myocardial infarction, cardiac arrest 
 • 
Respiratory: dyspnea 
• Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests 
• Dermatologic: hair loss, flushing, rash 
• Endocrine: decreased bone mineral density 
• Reproductive: menstrual irregularities, impaired fertility 
Seizures have been reported rarely with the institution of levothyroxine therapy. 
Adverse Reactions in Children: 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. 
Hypersensitivity Reactions: Hypersensitivity reactions to inactive ingredients have occurred in 
patients treated with thyroid hormone products. These include urticaria, pruritus, skin rash, 
flushing, angioedema, various gastrointestinal symptoms (abdominal pain, nausea, vomiting 
and diarrhea), fever, arthralgia, serum sickness, and wheezing. Hypersensitivity to 
levothyroxine itself is not known to occur. 
7 DRUG INTERACTIONS 
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics 
Many drugs can exert effects on thyroid hormone pharmacokinetics and metabolism (e.g., 
absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) 
and may alter the therapeutic response to levothyroxine sodium tablets (see Tables 2-5 
below). 
 


96 
 
TABLE 2. DRUGS THAT MAY DECREASE T4 ABSORPTION (HYPOTHYROIDISM) 
Potential impact: Concurrent use may reduce the efficacy of levothyroxine sodium tablets 
by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. 
 
Drug or Drug Class 
Effect 
Calcium Carbonate 
Calcium carbonate may form an insoluble chelate 
Ferrous Sulfate 
with levothyroxine, and ferrous sulfate likely forms 
a ferric-thyroxine complex. 
Administer levothyroxine sodium 
tablets at least 4 hours apart from 
these agents. 
Orlistat 
Monitor patients treated concomitantly with orlistat 
and levothyroxine sodium tablets for 
changes in thyroid function. 
Bile Acid Sequestrants Bile acid sequestrants and ion exchange resins are - Colesevelam 
known to decrease levothyroxine absorption. 
- Cholestyramine 
Administer levothyroxine sodium tablets at least 4 - Colestipol hours 
prior to these drugs or monitor TSH levels. 
Ion Exchange Resins 
- Kayexalate 
- Sevelamer 
Other Drugs: 
Gastric acidity is an essential requirement for 
Proton Pump Inhibitors 
adequate absorption of levothyroxine. Sucralfate, 
Sucralfate 
antacids and proton pump inhibitors may cause 
Antacids 
hypochlorhydria, affect intragastric pH, and reduce 
- Aluminum & Magnesium Hydroxides 
levothyroxine absorption. Monitor patients 
- Simethicone appropriately. 
  
TABLE 3. DRUGS THAT MAY ALTER T4 AND TRIIODOTHYRONINE (T3) SERUM TRANSPORT 
WITHOUT AFFECTING FREE THYROXINE (FT4) CONCENTRATION (EUTHYROIDISM) 
 
 
Clofibrate 
 
 
 
 
 
 
 
 
globulin (TBG) concentration. 
 
 
 
 


97 
 
Glucocorticoids 
Slow-Release Nicotinic Acid 
Potential impact (below): Administration of these agents with levothyroxine sodium 
tablets results in an initial transient increase in FT4. Continued administration results in a 
decrease in serum T4 and normal FT4 and TSH concentrations. 
Salicylates (> 2 g/day) 
Salicylates inhibit binding of T4 and T3 to TBG 
and transthyretin. An initial increase 
in serum FT4 is followed by return of 
FT4 to normal levels with sustained 
therapeutic serum salicylate 
concentrations, although total T4 
levels may decrease by as much as 
30%. 
Other drugs: 
These drugs may cause protein-binding site 
Carbamazepine Furosemide (> 80 mg IV) Heparin 
displacement. Furosemide has been 
shown to inhibit 
Hydantoins 
the protein binding of T4 to TBG and albumin, 
Non-Steroidal Anti-inflammatory Drugs 
causing an increase free T4 fraction in serum. 
- Fenamates 
Furosemide competes for T4-binding sites on 
TBG, prealbumin, and albumin, so that 
a single high dose can acutely lower 
the total T4 level. 
Phenytoin and carbamazepine reduce 
serum protein binding of levothyroxine, 
and total and free T4 may be reduced by 
20% to 40%, but most patients have 
normal serum TSH levels and are 
clinically euthyroid. Closely monitor 
thyroid hormone parameters. 
  
TABLE 4. DRUGS THAT MAY ALTER HEPATIC METABOLISM OF T4 (HYPOTHYROIDISM) 
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity 
may cause increased hepatic degradation of levothyroxine, resulting in increased 
levothyroxine sodium tablets requirements. 
 
Drug or Drug Class 
Effect 
Phenobarbital 
Phenobarbital has been shown to reduce the 
Rifampin 
 response to thyroxine. Phenobarbital increases L- 
thyroxine metabolism by inducing uridine 5’diphospho- 


98 
 
glucuronosyltransferase (UGT) and 
leads to a lower T4 serum levels. 
Changes in thyroid status may occur 
if barbiturates are added or 
withdrawn from patients being 
treated for hypothyroidism. 
Rifampin has been shown to 
accelerate the metabolism of 
levothyroxine. 
  
TABLE 5. DRUGS THAT MAY DECREASE CONVERSION OF T4 TO T3 
Potential impact: 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. 
 
Drug or Drug Class 
Effect 
Beta-adrenergic antagonists In patients treated with large doses of propranolol (e.g., 
Propranolol > 160 mg/day) (> 160 mg/day), T3 and T4 levels change, TSH 
levels remain normal, and patients 
are clinically euthyroid. Actions of 
particular beta-adrenergic 
antagonists may be impaired when 
a hypothyroid patient is converted 
to the euthyroid state. 
Glucocorticoids 
Short-term administration of large doses of (e.g., Dexamethasone 
≥ 4 mg/day) glucocorticoids may decrease serum T3 
concentrations by 30% with minimal 
change in serum T4 levels. However, 
long-term glucocorticoid therapy may 
result in slightly decreased T3 and T4 
levels due to decreased TBG 
production (See above). 
Other drugs: 
Amiodarone inhibits peripheral conversion of 
Amiodarone 
levothyroxine (T4) to triiodothyronine (T3) and 
may cause isolated biochemical 
changes (increase in serum free-T4, 
and decreased or normal freeT3) in 
clinically euthyroid patients. 


99 
 
7.2 Antidiabetic Therapy 
Addition of levothyroxine sodium tablets therapy in patients with diabetes mellitus may 
worsen glycemic control and result in increased antidiabetic agent or insulin 
requirements. Carefully monitor glycemic control, especially when thyroid therapy is 
started, changed, or discontinued [see Warnings and Precautions (5.5)]. 
7.3 Oral Anticoagulants 
Levothyroxine sodium tablets increase 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 levothyroxine sodium tablets dose is increased. Closely 
monitor coagulation tests to permit appropriate and timely dosage adjustments. 
7.4 Digitalis Glycosides 
Levothyroxine sodium tablets may reduce the therapeutic effects of digitalis glycosides. 
Serum digitalis glycoside levels may decrease when a hypothyroid patient becomes 
euthyroid, necessitating an increase in the dose of digitalis glycosides. 
7.5 Antidepressant Therapy 
Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) 
antidepressants and levothyroxine sodium tablets 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 central nervous system 
stimulation. Levothyroxine sodium tablets may accelerate the onset of action of tricyclics. 
Administration of sertraline in patients stabilized on levothyroxine sodium tablets may 
result in increased levothyroxine sodium tablets requirements. 
7.6 Ketamine 
Concurrent use of ketamine and levothyroxine sodium tablets may produce marked 
hypertension and tachycardia. Closely monitor blood pressure and heart rate in these 
patients. 
7.7 Sympathomimetics 
Concurrent use of sympathomimetics and levothyroxine sodium tablets 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. insufficiency when sympathomimetic agents are 
administered to patients with coronary artery disease. 
7.8 Tyrosine-Kinase Inhibitors 
Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. 
Closely monitor TSH levels in such patients. 


100 
 
 
 
 
7.9 Drug-Food Interactions 
Consumption of certain foods may affect levothyroxine sodium tablets absorption thereby 
necessitating adjustments in dosing [see Dosage and Administration (2.1)]. Soybean flour, 
cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of 
levothyroxine sodium tablets from the gastrointestinal tract. Grapefruit juice may delay 
the absorption of levothyroxine and reduce its bioavailability. 
7.10 Drug-Laboratory Test Interactions 
Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and 
evaluate unbound (free) hormone and/or determine the free-T4 index (FT4I) in this 
circumstance. Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral 
contraceptives, and acute intermittent porphyria increase TBG concentration. Nephrosis, 
severe hypoproteinemia, severe liver disease, acromegaly, androgens, and corticosteroids 
decrease TBG concentration. Familial hyper- or hypo-thyroxine binding globulinemias have 
been described, with the incidence of TBG deficiency approximating 1 in 9000. 
8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
Risk Summary 
Experience with levothyroxine use in pregnant women, including data from post-marketing 
studies, have not reported increased rates of major birth defects or miscarriages [see Data]. 
There are risks to the mother and fetus associated with untreated hypothyroidism in 
pregnancy. Since TSH levels may increase during pregnancy, TSH should be monitored and 
levothyroxine sodium tablets dosage adjusted during pregnancy [see Clinical 
Considerations]. There are no animal studies conducted with levothyroxine during 
pregnancy. Levothyroxine sodium tablets should not be discontinued during pregnancy and 
hypothyroidism diagnosed during pregnancy should be promptly treated. 
The estimated background risk of major birth defects and miscarriage for the indicated 
population is unknown. In the U.S. general population, the estimated background risk 
of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% 
and 15 to 20%, respectively.Clinical Considerations 
Disease-Associated Maternal and/or Embryo/Fetal Risk 


101 
 
Maternal hypothyroidism during pregnancy is associated with a higher rate of 
complications, including spontaneous abortion, gestational hypertension, pre-eclampsia, 
stillbirth, and premature delivery. Untreated maternal hypothyroidism may have an 
adverse effect on fetal neurocognitive development. 
Dose Adjustments During Pregnancy and the Postpartum Period 
Pregnancy may increase levothyroxine sodium tablets requirements. Serum TSH levels 
should be monitored and the levothyroxine sodium tablets dosage adjusted during 
pregnancy. Since postpartum TSH levels are similar to preconception values, the 
levothyroxine sodium tablets dosage should return to the pre-pregnancy dose 
immediately after delivery [see Dosage and Administration (2.3)]. 
Data 
Human Data 
Levothyroxine is approved for use as a replacement therapy for hypothyroidism. There is a 
long experience of levothyroxine use in pregnant women, including data from post-
marketing studies that have not reported increased rates of fetal malformations, 
miscarriages or other adverse maternal or fetal outcomes associated with levothyroxine 
use in pregnant women. 
8.2 Lactation 
Risk Summary 
Limited published studies report that levothyroxine is present in human milk. However, 
there is insufficient information to determine the effects of levothyroxine on the 
breastfed infant and no available information on the effects of levothyroxine on milk 
production. Adequate levothyroxine treatment during lactation may normalize milk 
production in hypothyroid lactating mothers. The developmental and health benefits of 
breastfeeding should be considered along with the mother’s clinical need for 
levothyroxine sodium tablets and any potential adverse effects on the breastfed infant 
from levothyroxine sodium tablets or from the underlying maternal condition. 
8.4 Pediatric Use 
The initial dose of levothyroxine sodium tablets varies with age and body weight. Dosing 
adjustments are based on an assessment of the individual patient's clinical and laboratory 
parameters [see Dosage and Administration (2.3, 2.4)]. 
In children in whom a diagnosis of permanent hypothyroidism has not been established, 
discontinue levothyroxine sodium tablets administration for a trial period, but only after 
the child is at least 3 years of age. Obtain serum T4 and TSH levels at the end of the trial 


102 
 
period, and use laboratory test results and clinical assessment to guide diagnosis and treatment, if 
warranted. 
Congenital Hypothyroidism 
[See Dosage and Administration (2.3, 2.4)] 
Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of 
congenital hypothyroidism on intellectual development as well as on overall physical growth and 
maturation. Therefore, initiate levothyroxine sodium tablets therapy immediately upon diagnosis. 
Levothyroxine is generally continued for life in these patients. 
Closely monitor infants during the first 2 weeks of levothyroxine sodium tablets therapy for cardiac 
overload, arrhythmias, and aspiration from avid suckling. 
Closely monitor patients to avoid undertreatment or overtreatment. Undertreatment may have 
deleterious effects on intellectual development and linear growth. Overtreatment is associated with 
craniosynostosis in infants, may adversely affect the tempo of brain maturation, and may accelerate the 
bone age and result in premature epiphyseal closure and compromised adult stature. 
Acquired Hypothyroidism in Pediatric Patients 
Closely monitor patients to avoid undertreatment and overtreatment. Undertreatment may result in 
poor school performance due to impaired concentration and slowed mentation and in reduced adult 
height. Overtreatment may accelerate the bone age and result in premature epiphyseal closure and 
compromised adult stature. 
Treated children may manifest a period of catch-up growth, which may be adequate in some cases to 
normalize adult height. In children with severe or prolonged hypothyroidism, catch-up growth may 
not be adequate to normalize adult height. 
8.5 Geriatric Use 
Because of the increased prevalence of cardiovascular disease among the elderly, initiate 
levothyroxine sodium tablets at less than the full replacement dose [see Warnings and Precautions 
(5.1)and Dosage and Administration (2.3)]. Atrial arrhythmias can occur in elderly patients. Atrial 
fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in 
the elderly. 
10 OVERDOSAGE 
The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and Precautions 
(5)and Adverse Reactions (6)]. In addition, confusion and disorientation may occur. Cerebral embolism, 
shock, coma, and death have been reported. Seizures occurred in a 3-year-old child ingesting 3.6 mg of 
levothyroxine. Symptoms may not necessarily be evident or may not appear until several days after 
ingestion of levothyroxine sodium. 
Reduce the levothyroxine sodium tablets dose or discontinue temporarily if signs or 
symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by 
the patient’s medical status. 
For current information on the management of poisoning or overdosage, contact the 
National Poison Control Center at 1-800-222-1222 or www.poison.org. 


103 
 
11 DESCRIPTION 
Levothyroxine sodium tablets, USP contain synthetic crystalline L-3,3',5,5'-
tetraiodothyronine sodium salt [levothyroxine (T4) sodium]. Synthetic T4 is chemically 
identical to that produced in the human thyroid gland. Levothyroxine (T4) sodium has a 
molecular formula of C15H10I4N NaO4 • H2O, molecular weight of 798.86 g/mol 
(anhydrous), and structural formula as shown: 
 
Levothyroxine sodium tablets for oral administration are supplied in the following 
strengths: 25 mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 
175 mcg, 200 mcg, and 300 mcg. Each levothyroxine sodium tablet contains the inactive 
ingredients butylated hydroxyanisole, colloidal silicon dioxide, crospovidone, magnesium 
stearate, mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate and sucrose. 
Table 6 provides a listing of the color additives by tablet strength: 
TABLE 6. LEVOTHYROXINE SODIUM TABLETS COLOR ADDITIVES 
 
Strength (mcg) 
Color additive(s) 
 
25 
FD&C Yellow No. 6 Aluminum Lake 
 
50 
None 
 
75 
FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake 
88 D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C 
Yellow No. 6 Aluminum Lake 
 
100 
D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake 
 
112 
D&C Red No. 27 Aluminum Lake, D&C Red No. 30 Aluminum Lake 
 
125 
FD&C Blue No. 1 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C 
Yellow No. 6 Aluminum Lake 
 
137 
FD&C Blue No. 2 Aluminum Lake 
 
150 
FD&C Blue No. 2 Aluminum Lake 
175 
D&C Red No. 27 Aluminum Lake, D&C Red No. 30 Aluminum Lake, 
FD&C Blue No. 1 Aluminum Lake 
 
200 
FD&C Red No. 40 Aluminum Lake 
300 D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C 
Yellow No. 6 Aluminum Lake 
12 CLINICAL PHARMACOLOGY 


104 
 
12.1 Mechanism of Action 
Thyroid hormones exert their physiologic actions through control of DNA transcription and 
protein synthesis. Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell nucleus 
and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor 
complex activates gene transcription and synthesis of messenger RNA and cytoplasmic 
proteins. 
The physiological actions of thyroid hormones are produced predominantly by T3, the 
majority of which (approximately 80%) is derived from T4 by deiodination in peripheral 
tissues. 
12.2 Pharmacodynamics 
Oral levothyroxine sodium is a synthetic T4 hormone that exerts the same 
physiologic effect as endogenous T4, thereby maintaining normal T4 levels when a 
deficiency is present.  
12.3 Pharmacokinetics 
Absorption 
Absorption of orally administered T4 from the gastrointestinal tract ranges from 40% to 
80%. The majority of the levothyroxine sodium tablets dose is absorbed from the jejunum 
and upper ileum. The relative bioavailability of levothyroxine sodium tablets, compared to 
an equal nominal dose of oral levothyroxine sodium solution, is approximately 93%. T4 
absorption is increased by fasting, and decreased in malabsorption syndromes and by 
certain foods such as soybeans. Dietary fiber decreases bioavailability of T4. Absorption 
may also decrease with age. In addition, many drugs and foods affect T4 absorption [see 
Drug Interactions (7)]. 
Distribution 
Circulating thyroid hormones are greater than 99% bound to plasma proteins, including 
thyroxinebinding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin 
(TBA), whose capacities and affinities vary for each hormone. The higher affinity of both 
TBG and TBPA for T4 partially explains the higher serum levels, slower metabolic 
clearance, and longer half-life of T4 compared to T3. Protein-bound thyroid hormones 
exist in reverse equilibrium with small amounts of free hormone. Only unbound hormone 
is metabolically active. Many drugs and physiologic conditions affect the binding of 
thyroid hormones to serum proteins [see Drug Interactions (7)]. Thyroid hormones do not 
readily cross the placental barrier [see Use in Specific Populations (8.1)]. 
Elimination 
5.7.1 Metabolism 


105 
 
T4 is slowly eliminated (see Table 7). The major pathway of thyroid hormone metabolism is 
through sequential deiodination. Approximately 80% of circulating T3 is derived from 
peripheral T4 by monodeiodination. The liver is the major site of degradation for both T4 
and T3, with T4 deiodination also occurring at a number of additional sites, including the 
kidney and other tissues. Approximately 80% of the daily dose of T4 is deiodinated to yield 
equal amounts of T3 and reverse T3 (rT3). T3 and rT3 are further deiodinated to 
diiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides 
and sulfates and excreted directly into the bile and gut where they undergo enterohepatic 
recirculation. 
5.7.2 Excretion 
Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated 
hormone reaches the colon unchanged and is eliminated in the feces. Approximately 20% 
of T4 is eliminated in the stool. Urinary excretion of T4 decreases with age. 
6 TABLE 7. PHARMACOKINETIC PARAMETERS OF THYROID HORMONES IN 
EUTHYROID PATIENTS 
* Includes TBG, TBPA, and TBA 
† 3 to 4 days in hyperthyroidism, 9 to 10 days in hypothyroidism 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
Standard animal studies have not been performed to evaluate the carcinogenic potential, 
mutagenic potential or effects on fertility of levothyroxine. 
16 HOW SUPPLIED/STORAGE AND HANDLING 
Levothyroxine Sodium Tablets, USP are available containing 25 mcg, 50 mcg, 75 mcg, 88 
mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 mcg or 300 mcg of 
levothyroxine sodium, USP. 
The 25 mcg tablets are orange, capsule-shaped, scored tablets debossed with L to the left 
of the score and 4 to the right of the score on one side of the tablet and M on the other 
side. 
NDC 0378-1800-77 
 
 
 
 
t 
 
 
 
  
 
 
 
6-7 
 
 
 
 
 
 
   
 
 


106 
 
bottles of 90 
tablets 
NDC 0378-1800-10 
bottles of 1000 tablets 
The 50 mcg tablets are white, capsule-shaped, scored tablets debossed with L to the left of 
the score and 5 to the right of the score on one side of the tablet and M on the other side. 
NDC 0378-
1803-77 
bottles of 90 
tablets 
NDC 0378-1803-10 
bottles of 1000 tablets 
The 75 mcg tablets are violet, capsule-shaped, scored tablets debossed with L to the left of 
the score and 6 to the right of the score on one side of the tablet and M on the other side. 
NDC 0378-1805-77 
bottles of 90 tablets 
NDC 0378-1805-10 
bottles of 1000 tablets 
The 88 mcg tablets are olive, capsule-shaped, scored tablets debossed with L to the left of 
the score and 7 to the right of the score on one side of the tablet and M on the other side. 
NDC 0378-1807-77 
bottles of 90 tablets 
NDC 0378-1807-10 
bottles of 1000 tablets 
The 100 mcg tablets are yellow, capsule-shaped, scored tablets debossed with L to the left 
of the score and 8 to the right of the score on one side of the tablet and M on the other 
side. 
NDC 0378-1809-77 
bottles of 90 tablets 
NDC 0378-1809-10 
bottles of 1000 tablets 
The 112 mcg tablets are rose, capsule-shaped, scored tablets debossed with L to the left of 
the score and 9 to the right of the score on one side of the tablet and M on the other side. 
NDC 0378-1811-77 
bottles of 90 tablets 
NDC 0378-1811-10 
bottles of 1000 tablets 
The 125 mcg tablets are gray, capsule-shaped, scored tablets debossed with L to the left of 
the score and 10 to the right of the score on one side of the tablet and M on the other side. 
NDC 0378-1813-77 
bottles of 90 tablets 
NDC 0378-1813-10 


107 
 
bottles of 1000 tablets 
The 137 mcg tablets are turquoise, capsule-shaped, scored tablets debossed with L to the 
left of the score and 15 to the right of the score on one side of the tablet and M on the 
other side. 
NDC 0378-
1823-77 
bottles of 90 
tablets 
NDC 0378-1823-10 
bottles of 1000 tablets 
The 150 mcg tablets are blue, capsule-shaped, scored tablets debossed with L to the left of 
the score and 11 to the right of the score on one side of the tablet and M on the other side. 
NDC 0378-1815-77 
bottles of 90 tablets 
NDC 0378-1815-10 
bottles of 1000 tablets 
The 175 mcg tablets are lilac, capsule-shaped, scored tablets debossed with L to the left of 
the score and 12 to the right of the score on one side of the tablet and M on the other side. 
NDC 0378-1817-77 
bottles of 90 tablets 
NDC 0378-1817-10 
bottles of 1000 tablets 
The 200 mcg tablets are pink, capsule-shaped, scored tablets debossed with L to the left of 
the score and 13 to the right of the score on one side of the tablet and M on the other side. 
NDC 0378-
1819-77 
bottles of 90 
tablets 
NDC 0378-1819-10 
bottles of 1000 tablets 
The 300 mcg tablets are green, capsule-shaped, scored tablets debossed with L to the left 
of the score and 14 to the right of the score on one side of the tablet and M on the other 
side. 
NDC 0378-1821-77 
bottles of 90 tablets 
NDC 0378-1821-10 
bottles of 1000 tablets 
Storage Conditions: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room 
Temperature.] Protect from light and moisture. 
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant 
closure. 


108 
 
PATIENT COUNSELING INFORMATION 
Inform the patient of the following information to aid in the safe and effective use of 
levothyroxine sodium tablets: 
Dosing and Administration: 
• Instruct patients to take levothyroxine sodium tablets only as directed by their 
healthcare provider. 
• Instruct patients to take levothyroxine sodium tablets as a single dose, preferably on 
an empty stomach, one-half to one hour before breakfast. 
• Inform patients that agents such as iron and calcium supplements and antacids can 
decrease the absorption of levothyroxine. Instruct patients not to take levothyroxine 
sodium tablets within 4 hours of these agents. 
• Instruct patients to notify their healthcare provider if they are pregnant or 
breastfeeding or are thinking of becoming pregnant while taking levothyroxine sodium 
tablets. 
Important Information: 
• Inform patients that it may take several weeks before they notice an improvement in 
symptoms. 
• Inform patients that the levothyroxine in levothyroxine sodium tablets is intended to 
replace a hormone that is normally produced by the thyroid gland. Generally, 
replacement therapy is to be taken for life. 
• Inform patients that levothyroxine sodium tablets should not be used as a primary or 
adjunctive therapy in a weight control program. 
• Instruct patients to notify their healthcare provider if they are taking any other 
medications, including prescription and over-the-counter preparations. 
• Instruct patients to notify their physician of any other medical conditions they may 
have, particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary 
gland problems, as the dose of medications used to control these other conditions may 
need to be adjusted while they are taking levothyroxine sodium tablets. If they have 
diabetes, instruct patients to monitor their blood and/or urinary glucose levels as 
directed by their physician and immediately report any 
 
 
 
 
 


109 
 
changes to their physician. If patients are taking anticoagulants, their clotting status 
should be checked frequently. 
• Instruct patients to notify their physician or dentist that they are taking levothyroxine 
sodium tablets prior to any surgery. 
Adverse Reactions: 
• Instruct patients to notify their healthcare provider if they experience any of the 
following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, leg 
cramps, headache, nervousness, irritability, sleeplessness, tremors, change in appetite, 
weight gain or loss, vomiting, diarrhea, excessive sweating, heat intolerance, fever, 
changes in menstrual periods, hives or skin rash, or any other unusual medical event. 
• Inform patients that partial hair loss may occur rarely during the first few months of 
levothyroxine sodium tablets therapy, but this is usually temporary. 
U.S. Patent No. 6,645,526 
U.S. Patent No. 6,936,274 
U.S. Patent No. 7,052,717 
U.S. Patent No. 7,195,779 
Mylan Pharmaceuticals Inc. 
Morgantown, WV 26505 U.S.A. 
Revised: 10/2017 
LVTX:R13 
 
 
 
 
 
 
 
 
 
 
 
 


110 
 
PRINCIPAL DISPLAY PANEL - 25 mcg (0.025 mg) 
NDC 0378-1800-77 
Levothyroxine  Sodium 
Tablets, USP 25 mcg (0.025 mg) 
Rx only 90 Tablets 
Each  
Tablet 
contains: 
Levothyro
xine 
sodium, 
USP 25 
mcg 
Dispense in a tight, 
light-resistant 
container as defined 
in the USP using a 
child-resistant 
closure. 
Keep container tightly closed. 
Keep this and all 
medication out of 
the reach of 
children. 
Store at 20° to 25°C (68° to 77°F). 
[See USP Controlled Room 
Temperature.] 
Protect from light and moisture. 
Usual Dosage: 
prescribing information. 
U.S. Patent Nos. 6,645,526; 
6,936,274; 7,052,717; 7,195,779 
Mylan Pharmaceuticals Inc. 
Morgantown, WV 26505 U.S.A. 
Mylan.com 
RM1800MM1 
 
 


111 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


112 
 
PRINCIPAL DISPLAY PANEL - 50 mcg (0.05 mg) 
NDC 0378-1803-77 
Levothyroxine Sodium 
Tablets, USP 50 mcg (0.5 mg) 
Rx only 90 Tablets 
Each 
tablet 
contains: 
Levothyro
xine 
sodium, 
USP 50 
mcg 
Dispense in a tight, 
light-resistant 
container as defined 
in the USP using a 
child-resistant 
closure. 
Keep container tightly closed. 
Keep this and all 
medication out of the 
reach of children. 
Store at 20° to 25°C (68° to 77°F). 
[See USP Controlled Room 
Temperature.] 
Protect from light and moisture. 
Usual Dosage: 
prescribing information. 
prescribing information. 
U.S. Patent Nos. 6,645,526; 
6,936,274; 7,052,717; 7,195,779 
Mylan Pharmaceuticals Inc. 
Morgantown, WV 26505 U.S.A. 
Mylan.com 
RM1803MM1 
 
 


113 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


114 
 
 
PRINCIPAL DISPLAY PANEL - 75 mcg (0.075 mg) 
NDC 0378-1805-77 
Levothyroxine Sodium Tablets, USP 
75 mcg (0.075 mg) 
Rx only 90 Tablets 
Each 
tablet 
contains: 
Levothyro
xine 
sodium, 
USP 75 
mcg 
Dispense in a tight, 
light-resistant 
container as defined 
in the USP using a 
child-resistant 
closure. 
Keep container tightly closed. 
Keep this and all 
medication out of 
the reach of 
children. 
Store at 20° to 25°C (68° to 77°F). 
[See USP Controlled Room 
Temperature.] 
Protect from light and moisture. 
Usual Dosage: 
prescribing information. 
U.S. Patent Nos. 6,645,526; 6,936,274; 7,052,717; 7,195,779 
Mylan Pharmaceuticals Inc. 
Morgantown, WV 26505 U.S.A. 
Mylan.com 
RM1805MM1 
 


115 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


116 
 
 
PRINCIPAL DISPLAY PANEL - 88 mcg (0.088 mg) 
NDC 0378-1807-77 
Levothyroxine 
Sodium 
Tablets, USP 
88 mcg 
(0.088 mg) 
Rx only 90 Tablets 
Each tablet contains: Levothyroxine sodium, USP 88 mcg 
Dispense in a tight, light-resistant container as defined in the USP 
using a child-resistant closure. 
Keep container tightly closed. 
Keep this and all medication out of the reach of children. 
Store at 20° to 25°C (68° to 77°F). 
[See USP Controlled Room Temperature.] 
Protect from light and moisture. 
Usual Dosage: See accompanying 
Usual Dosage: See accompanying prescribing information. 
U.S. Patent Nos. 6,645,526; 6,936,274; 7,052,717; 7,195,779 
Mylan Pharmaceuticals Inc. 
Morgantown, WV 26505 U.S.A. 
Mylan.com 
RM1807MM1 
 
 
 
 
 
 
 
 
 


117 
 
 
 
 
PRINCIPAL DISPLAY PANEL - 100 mcg (0.1 mg) 
NDC 0378-1809-77 
Levothyroxine 
Sodium 
Tablets, USP 
100 mcg (0.1 mg) 
Rx only 90 Tablets 
Each tablet contains: Levothyroxine sodium, USP 100 mcg 
Dispense in a tight, light-resistant container as defined in the USP using a 
child-resistant closure. 
Keep container tightly closed. 
Keep this and all medication out of the reach of children. 
Store at 20° to 25°C (68° to 77°F). 
[See USP Controlled Room Temperature.] 
Protect from light and moisture. 
RM1809MM1 
 
 
 
 
 


118 
 
 
 
 
 
PRINCIPAL DISPLAY PANEL - 112 mcg (0.112 mg) 
NDC 0378-1811-77 
Levothyroxine 
Sodium 
Tablets, USP 
112 mcg 
(0.112 mg) 
Rx only 90 Tablets 
Each tablet contains: Levothyroxine sodium, USP 112 
mcg 
Dispense in a tight, light-resistant container as defined in the USP 
using a child-resistant closure. 
 
 
 
 
 
 
 
 


119 
 
 
 
 
 
 
PRINCIPAL DISPLAY PANEL - 125 mcg (0.125 mg) 
NDC 0378-1813-77 
Levothyroxine 
Sodium 
Tablets, USP 
125 mcg 
(0.125 mg) 
Rx only 90 Tablets 
Each tablet contains: Levothyroxine sodium, USP 125 
mcg 
Dispense in a tight, light-resistant container as defined in the USP 
using a child-resistant closure. 
RM1813MM1 
 
 
 
 
 
 


120 
 
 
 
 
 
PRINCIPAL DISPLAY PANEL - 137 mcg (0.137 mg) 
NDC 0378-1823-77 
Levothyroxine 
Sodium 
Tablets, USP 
137 mcg 
(0.137 mg) 
Rx only 90 Tablets 
Each tablet contains: Levothyroxine sodium, USP 137 
mcg 
Dispense in a tight, light-resistant container as defined in the USP 
using a child-resistant closure. 
RM1823MM1 
Usual Dosage: See accompanying prescribing information. 
 
 
 
 
 
 


121 
 
U.S. Patent Nos. 6,645,526; 6,936,274; 7,052,717; 7,195,779 
Mylan Pharmaceuticals Inc. 
Morgantown, WV 26505 U.S.A. 
Mylan.com 
Each tablet contains: Levothyroxine sodium, USP 137 
mcg 
Dispense in a tight, light-resistant container as defined in the USP 
using a child-resistant closure. 
RM1823MM1 
 
 
 
PRINCIPAL DISPLAY PANEL - 150 mcg (0.15 mg) 
NDC 0378-1815-77 
Levothyroxine 
Sodium 
Tablets, USP 
 
 
 
 
 
 
 


122 
 
 
PRINCIPAL DISPLAY PANEL - 150 mcg (0.15 mg) 
NDC 0378-1815-77 
Levothyroxine 
Sodium 
Tablets, USP 
 
 
 
 
PRINCIPAL DISPLAY PANEL - 175 mcg (0.175 mg) 
NDC 0378-1817-77 
Levothyroxine 
Sodium 
Tablets, USP 
175 mcg 
(0.175 mg) 
Rx only 90 Tablets 
Each tablet contains: Levothyroxine sodium, USP 175 
mcg 
 
 
 
 


123 
 
Dispense in a tight, light-resistant container as defined in the USP 
using a child-resistant closure. 
  
Usual Dosage: See accompanying prescribing information. 
U.S. Patent Nos. 6,645,526; 6,936,274; 7,052,717; 7,195,779 
Mylan Pharmaceuticals Inc. 
Morgantown, WV 26505 U.S.A. 
Mylan.com 
 
RM1817MM1 
 
 
 
 
 
 
 
 
 
 
 
 
 


124 
 
 
PRINCIPAL DISPLAY PANEL - 200 mcg (0.2 mg) 
NDC 0378-1819-77 
Levothyroxine 
Sodium 
Tablets, USP 
200 mcg (0.2 mg) 
Rx only 90 Tablets 
Each tablet contains: Levothyroxine sodium, USP 200 
mcg 
Dispense in a tight, light-resistant 
container as defined in the USP 
using a child-resistant Usual 
Dosage: See accompanying 
prescribing information. 
U.S. Patent Nos. 6,645,526; 
6,936,274; 7,052,717; 7,195,779 
Mylan Pharmaceuticals Inc. 
Morgantown, WV 26505 U.S.A. 
Mylan.com 
RM1819MM1 
 
 
 
 
 
 


125 
 
PRINCIPAL DISPLAY PANEL - 300 mcg (0.3 mg) 
NDC 0378-1821-77 
Levothyroxine 
Sodium 
Tablets, USP 
300 mcg (0.3 mg) 
Rx only 90 Tablets 
Each tablet contains: Levothyroxine sodium, USP 300 mcg 
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant 
closure. 
Keep container tightly closed 
Rx only 90 Tablets 
 
Keep this and all 
medication out of 
the reach of 
children. 
Store at 20° to 25°C (68° to 77°F). 
[See USP Controlled Room 
Temperature.] 
Protect from light and moisture. 
Usual Dosage: See accompanying 
prescribing information. 
U.S. Patent Nos. 6,645,526; 
6,936,274; 7,052,717; 7,195,779 
Mylan Pharmaceuticals Inc. 
Morgantown, WV 26505 U.S.A. 
Mylan.com 
RM1821MM1 


126 
 
 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0378-1800 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
 
 
 
 
 
 
 
 
 
 
 
 
 


127 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
25 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
MANNITOL (UNII: 3OWL53L36A) 
 
  
 
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) 
 
  
POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) 
 
  
SODIUM LAURYL SULFATE (UNII: 368GB5141J) 
 
  
SUCROSE (UNII: C151H8M554) 
 
  
FD&C YELLOW NO. 6 (UNII: H77VEI93A8) 
 
  
 
 
Product Characteristics 
 
Color 
ORANGE 
Score 
 
2 pieces 
Shape 
OVAL (capsule-shaped) 
Size 
 
9mm 
Flavor 
 
Imprint Code 
 
M;L;4 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start 
Date 
 
Marketing End 
Date 


128 
 
1 NDC:0378-1800- 
77 
90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 
08/01/2016 
  
2 NDC:0378-1800- 
10 
1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
11/01/2002 
  
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA076187 
11/01/2002 
 
 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0378-1803 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
50 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
 
MANNITOL (UNII: 3OWL53L36A) 
 
  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) 
 
  


129 
 
POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) 
 
  
SODIUM LAURYL SULFATE (UNII: 368GB5141J) 
 
  
SUCROSE (UNII: C151H8M554) 
 
  
 
 
Product Characteristics 
 
Color 
WHITE 
Score 
 
2 pieces 
Shape 
OVAL (capsule-shaped) 
Size 
 
9mm 
Flavor 
 
Imprint Code 
 
M;L;5 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start 
Date 
 
Marketing End 
Date 
1 NDC:0378-1803- 
77 
90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 
06/28/2016 
  
2 
NDC:0378-1803- 
10 
1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
11/01/2002 
  
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA076187 
11/01/2002 
 
 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0378-1805 
Route of Administration 
ORAL 


130 
 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
75 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
 
MANNITOL (UNII: 3OWL53L36A) 
 
  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) 
 
  
POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) 
 
  
SODIUM LAURYL SULFATE (UNII: 368GB5141J) 
 
  
SUCROSE (UNII: C151H8M554) 
 
  
FD&C BLUE NO. 2 (UNII: L06K8R7DQK) 
 
  
FD&C RED NO. 40 (UNII: WZB9127XOA) 
 
  
 
 
Product Characteristics 
 
Color 
PURPLE (violet) 
Score 
 
2 pieces 
Shape 
OVAL (capsule-shaped) 
Size 
 
9mm 
Flavor 
 
Imprint Code 
 
M;L;6 
Contains 
     


131 
 
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start 
Date 
 
Marketing End 
Date 
1 NDC:0378-1805- 
77 
90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 
06/16/2016 
  
2 
NDC:0378-1805- 
10 
1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
11/01/2002 
  
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA076187 
11/01/2002 
 
 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0378-1807 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
88 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 


132 
 
BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
 
CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
MANNITOL (UNII: 3OWL53L36A) 
 
  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) 
 
  
POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) 
 
  
SODIUM LAURYL SULFATE (UNII: 368GB5141J) 
 
  
SUCROSE (UNII: C151H8M554) 
 
  
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) 
 
  
FD&C BLUE NO. 1 (UNII: H3R47K3TBD) 
 
  
FD&C YELLOW NO. 6 (UNII: H77VEI93A8) 
 
  
 
 
Product Characteristics 
 
Color 
GREEN (olive) 
Score 
 
2 pieces 
Shape 
OVAL (capsule-shaped) 
Size 
 
9mm 
Flavor 
 
Imprint Code 
 
M;L;7 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start 
Date 
 
Marketing End 
Date 
1 NDC:0378-1807- 
77 
90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 
06/27/2016 
  
2 
NDC:0378-1807- 
10 
1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
11/01/2002 
  


133 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA076187 
11/01/2002 
 
 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0378-1809 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
100 ug 
 
 
Inactive Ingredients 
 
 
Ingredient Name 
 
Strength 
BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
MANNITOL (UNII: 3OWL53L36A) 
 
  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) 
 
  


134 
 
POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) 
 
  
SODIUM LAURYL SULFATE (UNII: 368GB5141J) 
 
  
SUCROSE (UNII: C151H8M554) 
 
  
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) 
 
  
FD&C YELLOW NO. 6 (UNII: H77VEI93A8) 
 
  
 
 
Product Characteristics 
 
Color 
YELLOW 
Score 
 
2 pieces 
Shape 
OVAL (capsule-shaped) 
Size 
 
9mm 
Flavor 
 
Imprint Code 
 
M;L;8 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start 
Date 
 
Marketing End 
Date 
1 NDC:0378-1809- 
77 
90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 
09/27/2016 
  
2 NDC:0378-1809- 
10 
1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
11/01/2002 
  
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA076187 
11/01/2002 
 
 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 


135 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0378-1811 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
112 ug 
 
 
 
Inactive Ingredients 
 
 
Ingredient Name 
 
 
Strength 
BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) 
 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
 
  
CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) 
 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
 
  
MANNITOL (UNII: 3OWL53L36A) 
 
 
  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) 
 
 
  
POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) 
 
 
  
SODIUM LAURYL SULFATE (UNII: 368GB5141J) 
 
 
  
SUCROSE (UNII: C151H8M554) 
 
 
  
D&C RED NO. 27 (UNII: 2LRS185U6K) 
 
 
  
D&C RED NO. 30 (UNII: 2S42T2808B) 
 
 
  
 
 
 
Product Characteristics 
 
 


136 
 
Color 
PINK (rose) 
Score 
 
2 pieces 
Shape 
OVAL (capsule-shaped) 
Size 
 
9mm 
Flavor 
 
Imprint Code 
 
M;L;9 
Contains 
     
 
 
 
Packaging 
 
 
# 
Item Code 
Package Description 
 
Marketing Start Date  
Marketing End Date 
1 NDC:0378-1811- 
77 
90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
 
06/27/2016 
  
2 
NDC:0378-1811- 
10 
1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
 
11/01/2002 
  
 
 
 
Marketing Information 
 
 
Marketing Category 
Application Number or Monograph Citation  
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA076187 
 11/01/2002 
 
 
 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0378-1813 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
 


137 
 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
125 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
MANNITOL (UNII: 3OWL53L36A) 
 
  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) 
 
  
POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) 
 
  
SODIUM LAURYL SULFATE (UNII: 368GB5141J) 
 
  
SUCROSE (UNII: C151H8M554) 
 
  
FD&C BLUE NO. 1 (UNII: H3R47K3TBD) 
 
  
FD&C RED NO. 40 (UNII: WZB9127XOA) 
 
  
FD&C YELLOW NO. 6 (UNII: H77VEI93A8) 
 
  
 
 
Product Characteristics 
 
Color 
GRAY 
Score 
2 pieces 
Shape 
OVAL (capsule-shaped) 
Size 
9mm 
Flavor 
 
Imprint Code 
M;L;10 
Contains 
     
 
 
Packaging 
 
# 
Item Code 
Package Description 
 
Marketing Start 
Date 
Marketing End Date 
1 NDC:0378-1813- 
77 
90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
 
05/27/2016 
 


138 
 
2 
NDC:0378-1813- 
10 
1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
 
11/01/2002 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation  
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA076187 
 11/01/2002 
 
 
 
 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
137 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
MANNITOL (UNII: 3OWL53L36A) 
 
  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) 
 
  
 
 
 
 
 
 
 
 
 


139 
 
POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) 
 
  
SODIUM LAURYL SULFATE (UNII: 368GB5141J) 
 
  
SUCROSE (UNII: C151H8M554) 
 
  
FD&C BLUE NO. 2 (UNII: L06K8R7DQK) 
 
  
 
 
Product Characteristics 
 
Color 
TURQUOISE 
Score 
2 pieces 
Shape 
OVAL (capsule-shaped) 
Size 
9mm 
Flavor 
 
Imprint Code 
M;L;15 
Contains 
     
 
 
Packaging 
 
# 
Item Code 
Package Description 
 
Marketing Start 
Date 
Marketing End Date 
1 NDC:0378-1823- 
77 
90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
 
06/16/2016 
 
2 
NDC:0378-1823- 
10 
1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
 
02/26/2008 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation  
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA076187 
 12/15/2006 
 
 
 


140 
 
 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
150 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
MANNITOL (UNII: 3OWL53L36A) 
 
  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) 
 
  
POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) 
 
  
SODIUM LAURYL SULFATE (UNII: 368GB5141J) 
 
  
SUCROSE (UNII: C151H8M554) 
 
  
FD&C BLUE NO. 2 (UNII: L06K8R7DQK) 
 
  
 
 
Product Characteristics 
 
 
 
 
 
 
 
 
 
 


141 
 
Color 
BLUE 
Score 
2 pieces 
Shape 
OVAL (capsule-shaped) 
Size 
9mm 
Flavor 
 
Imprint Code 
M;L;11 
Contains 
     
 
 
Packaging 
 
# 
Item Code 
Package Description 
 
Marketing Start 
Date 
Marketing End Date 
1 NDC:0378-1815- 
77 
90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
 
06/27/2016 
 
2 
NDC:0378-1815- 
10 
1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
 
11/01/2002 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation  
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA076187 
 11/01/2002 
 
 
 
 
 
 
 
 
 
 
 


142 
 
 


143 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
 
Item Code (Source) 
NDC:0378-1819 
Route of Administration 
ORAL 
  
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
200 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
MANNITOL (UNII: 3OWL53L36A) 
 
  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) 
 
  
POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) 
 
  
SODIUM LAURYL SULFATE (UNII: 368GB5141J) 
 
  
SUCROSE (UNII: C151H8M554) 
 
  
FD&C RED NO. 40 (UNII: WZB9127XOA) 
 
  


144 
 
 
 
Product Characteristics 
 
Color 
PINK 
Score 
2 pieces 
Shape 
OVAL (capsule-shaped) 
Size 
9mm 
Flavor 
 
Imprint Code 
M;L;13 
Contains 
     
 
 
Packaging 
 
# 
Item Code 
Package Description 
 
Marketing Start 
Date 
Marketing End Date 
1 NDC:0378-1819- 
77 
90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
 
08/10/2016 
 
2 NDC:0378-1819- 
10 
1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
 
11/01/2002 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation  
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA076187 
 11/01/2002 
 
 
 
 
6.1 
levothyroxine sodium tablet 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
 
Item Code (Source) 
NDC:0378-1821 
Route of Administration 
ORAL 
  
 
 
 
 


145 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
300 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
MANNITOL (UNII: 3OWL53L36A) 
 
  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) 
 
  
POVIDONE, UNSPECIFIED (UNII: FZ989GH94E) 
 
  
SODIUM LAURYL SULFATE (UNII: 368GB5141J) 
 
  
SUCROSE (UNII: C151H8M554) 
 
  
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) 
 
  
FD&C BLUE NO. 1 (UNII: H3R47K3TBD) 
 
  
FD&C YELLOW NO. 6 (UNII: H77VEI93A8) 
 
  
 
 
Product Characteristics 
 
Color 
GREEN 
Score 
2 pieces 
Shape 
OVAL (capsule-shaped) 
Size 
9mm 
Flavor 
 
Imprint Code 
M;L;14 
Contains 
     


146 
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
 
Marketing Start Date 
Marketing End Date 
1 NDC:0378-1821- 
77 
90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
 
05/27/2016 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation  
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA076187 
 
11/01/2002 
 
 
 
Labeler - Mylan Pharmaceuticals Inc. (059295980) 
Revised: 10/2017  
Mylan Pharmaceuticals Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


147 
 
Appendix D 
LEVOTHYROXINE SODIUM- LEVOTHYROXINE SODIUM 
TABLET  LEVOTHYROXINE SODIUM- LEVOTHYROXINE 
SODIUM TABLET  SANDOZ INC. 
---------- 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use LEVOTHYROXINE 
SODIUM TABLETS safely and effectively. See full prescribing information for 
LEVOTHYROXINE SODIUM TABLETS.  
LEVOTHYROXINE SODIUM tablets, for oral use  
Initial U.S. Approval: 2002 
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS 
See full prescribing information for complete boxed warning  
• 
Thyroid hormones, including levothyroxine sodium tablets should not be used for 
the treatment ofobesity or for weight loss.  
• 
Doses beyond the range of daily hormonal requirements may produce serious or 
even life threateningmanifestations of toxicity (6, 10). 
 
Levothyroxine sodium tablets is L-thyroxine (T4) indicated for:  
• 
Hypothyroidism: As replacement therapy in primary (thyroidal), secondary (pituitary) 
and tertiary (hypothalamic)congenital or acquired hypothyroidism. (1)  
• 
Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression: As an 
adjunct to surgery and radioiodinetherapy in the management of thyrotropin-dependent 
well-differentiated thyroid cancer. (1) Limitations of Use:  
- Not indicated for suppression of benign thyroid nodules and nontoxic diffuse 
goiter in iodine-sufficient patients. - Not indicated for treatment of 
hypothyroidism during the recovery phase of subacute thyroiditis. (1) 
 
• Administer once daily, preferably on an empty stomach, one-half to one hour before 
breakfast. (2.1)  
• Administer at least 4 hours before or after drugs that are known to interfere with 
absorption. (2.1)  
• Evaluate the need for dose adjustments when regularly administering within one hour of 
certain foods that may affectabsorption. (2.1)  
 
 


148 
 
• Starting dose depends on a variety of factors, including age, body weight, cardiovascular 
status and concomitantmedications. Peak therapeutic effect may not be attained for 4-6 
weeks. (2.2)  
• See full prescribing information for dosing in specific patient populations. (2.3)  
• Adequacy of therapy determined with periodic monitoring of TSH and/or T4 as well as 
clinical status. (2.4) (2) 
 
• Cardiac adverse reactions in the elderly and in patients with underlying cardiovascular 
disease: Initiate levothyroxine sodium tablets at less than the full replacement dose 
because of the increased risk of cardiac adverse reactions, including atrial fibrillation. (2.3, 
5.1, 8.5)  
• Myxedema coma: Do not use oral thyroid hormone drug products to treat myxedema coma. (5.2)  
• Acute adrenal crisis in patients with concomitant adrenal insufficiency: Treat with replacement glucocorticoids 
prior to initiation of levothyroxine sodium tablets treatment. (5.3)  
• Prevention of hyperthyroidism or incomplete treatment of hypothyroidism: Proper dose titration and careful 
monitoring is critical to prevent the persistence of hypothyroidism or the development of hyperthyroidism. 
(5.4)  
• Worsening of diabetic control: Therapy in patients with diabetes mellitus may worsen glycemic control and 
result in increased antidiabetic agent or insulin requirements. Carefully monitor glycemic control after 
starting, changing or discontinuing thyroid hormone therapy. (5.5)  
• Decreased bone mineral density associated with thyroid hormone over- replacement: Over-replacement can 
increase bone resorption and decrease bone mineral density. Give the lowest effective dose. (5.6) (5) 
 
Adverse reactions associated with levothyroxine sodium tablets therapy are primarily those of 
hyperthyroidism due to therapeutic overdosage: arrhythmias, myocardial infarction, dyspnea, muscle 
spasm, headache, nervousness, irritability, insomnia, tremors, muscle weakness, increased appetite, 
weight loss, diarrhea, heat intolerance, menstrual irregularities and skin rash. (6) (6) 
To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA1088 
or www.fda.gov/medwatch. (6) 
 
See full prescribing information for drugs that affect thyroid hormone pharmacokinetics and 
metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding and target tissue 
response) and may alter the therapeutic response to levothyroxine sodium tablets. (7) (7) 
 
Pregnancy may require the use of higher doses of levothyroxine sodium tablets. (2.3, 8.1) (8) 
See 17 for PATIENT COUNSELING INFORMATION. 
Revised: 12/2017 
 
 
 
   
 
    
 
 
 
 


149 
 
FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: NOT FOR TREATMENT OF 
OBESITY OR FOR WEIGHT LOSS 1 INDICATIONS AND USAGE 2 DOSAGE AND 
ADMINISTRATION 
2.1 General Administration Information 2.2 General Principles of Dosing 2.3 Dosing in Specific 
Patient Populations 2.4 Monitoring TSH and/or Thyroxine (T4) Levels 
3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND 
PRECAUTIONS 
5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular 
Disease 5.2 Myxedema Coma 5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal 
Insufficiency 5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism 5.5 
Worsening of Diabetic Control 5.6 Decreased Bone Mineral Density Associated with Thyroid 
Hormone Over-Replacement 
6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics 7.2 Antidiabetic Therapy 7.3 Oral 
Anticoagulants 7.4 Digitalis Glycosides 7.5 Antidepressant Therapy 7.6 Ketamine 7.7 
Sympathomimetics 7.8 Tyrosine-Kinase Inhibitors 7.9 Drug-Food Interactions 7.10 Drug-Laboratory 
Test Interactions 
8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 
10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
12.2 Pharmacodynamics 12.3 Pharmacokinetics 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 


150 
 
16 HOW SUPPLIED/STORAGE AND  
HANDLING  
17 PATIENT COUNSELING INFORMATION 
* Sections or subsections omitted from the full prescribing information are not listed. 
 
FULL PRESCRIBING INFORMATION 
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS 
Thyroid hormones, including levothyroxine sodium tablets, either alone or with other 
therapeutic agents, should not be used for the treatment of obesity or for weight loss. 
In euthyroid patients, doses within the range of daily hormonal requirements are ineffective 
for weight reduction. 
Larger doses may produce serious or even life threatening manifestations of toxicity, 
particularly when given in association with sympathomimetic amines such as those used for 
their anorectic effects [see Adverse Reactions (6), Drug Interactions (7.7) and Overdosage (10)]. 
1 INDICATIONS AND USAGE HYPOTHYROIDISM  
Levothyroxine sodium tablets are indicated as a replacement therapy in primary (thyroidal), 
secondary (pituitary) and tertiary (hypothalamic) congenital or acquired hypothyroidism. 
PITUITARY THYROTROPIN (THYROID-STIMULATING HORMONE, TSH) SUPPRESSION 
Levothyroxine sodium tablets are indicated as an adjunct to surgery and radioiodine therapy in 
the management of thyrotropin-dependent well-differentiated thyroid cancer. 
Limitations of Use:  
• 
Levothyroxine sodium tablets are not indicated for suppression of benign thyroid nodules 
and nontoxicdiffuse goiter in iodine-sufficient patients as there are no clinical benefits and 
overtreatment with levothyroxine sodium tablets may induce hyperthyroidism [see Warnings and 
Precautions (5.4)]. 
• 
Levothyroxine sodium tablets are not indicated for treatment of hypothyroidism during the 
recoveryphase of subacute thyroiditis. 
 
 
 


151 
 
2 DOSAGE AND ADMINISTRATION 
2.1 General Administration Information 
Take levothyroxine sodium tablets with a full glass of water as the tablet may rapidly 
disintegrate. 
Administer levothyroxine sodium tablets as a single daily dose, on an empty stomach, one-half 
to one hour before breakfast. 
Administer levothyroxine sodium tablets at least 4 hours before or after drugs known to interfere 
with levothyroxine sodium tablets absorption [see Drug Interactions (7.1)]. 
Evaluate the need for dose adjustments when regularly administering within one hour of 
certain foods that may affect levothyroxine sodium tablets absorption [see Drug Interactions 
(7.9) and Clinical Pharmacology (12.3)]. 
Administer levothyroxine sodium tablets to infants and children who cannot swallow intact 
tablets by crushing the tablet, suspending the freshly crushed tablet in a small amount (5 to 10 
mL or 1 to 2 teaspoons) of water and immediately administering the suspension by spoon or 
dropper. Do not store the suspension. Do not administer in foods that decrease absorption of 
levothyroxine sodium tablets, such as soybean-based infant formula [see Drug Interactions (7.9)]. 
2.2 General Principles of Dosing 
The dose of levothyroxine sodium tablets for hypothyroidism or pituitary TSH suppression 
depends on a variety of factors including: the patient's age, body weight, cardiovascular status, 
concomitant medical conditions (including pregnancy), concomitant medications, co-
administered food and the specific nature of the condition being treated [see Dosage and 
Administration (2.3), Warnings and Precautions (5) and Drug Interactions (7)]. Dosing must be 
individualized to account for these factors and dose adjustments made based on periodic 
assessment of the patient's clinical response and laboratory parameters [see Dosage and 
Administration (2.4)]. 
The peak therapeutic effect of a given dose of levothyroxine sodium tablets may not be attained 
for 4 to 6 weeks. 
2.3 Dosing in Specific Patient Populations 
Primary Hypothyroidism in Adults and in Adolescents in Whom Growth and Puberty are Complete 
Start levothyroxine sodium tablets at the full replacement dose in otherwise healthy, non-elderly 
individuals who have been hypothyroid for only a short time (such as a few months). The 
average full replacement dose of levothyroxine sodium tablets is approximately 1.6 mcg per kg 
per day (for example: 100 to 125 mcg per day for a 70 kg adult). 
Adjust the dose by 12.5 to 25 mcg increments every 4 to 6 weeks until the patient is clinically 
euthyroid and the serum TSH returns to normal. Doses greater than 200 mcg per day are 
seldom required. An inadequate response to daily doses of greater than 300 mcg per day is 
rare and may indicate poor compliance, malabsorption, drug interactions or a combination of 
these factors. 
For elderly patients or patients with underlying cardiac disease, start with a dose of 12.5 to 25 
mcg per day. Increase the dose every 6 to 8 weeks, as needed until the patient is clinically 
euthyroid and the serum TSH returns to normal. The full replacement dose of levothyroxine 
sodium tablets may be less than 1 mcg per kg per day in elderly patients. 


152 
 
In patients with severe longstanding hypothyroidism, start with a dose of 12.5 to 25 mcg per 
day. Adjust the dose in 12.5 to 25 mcg increments every 2 to 4 weeks until the patient is 
clinically euthyroid and the serum TSH level is normalized. 
Secondary or Tertiary Hypothyroidism 
Start levothyroxine sodium tablets at the full replacement dose in otherwise healthy, non-elderly 
individuals. Start with a lower dose in elderly patients, patients with underlying cardiovascular 
disease or patients with severe longstanding hypothyroidism as described above. Serum TSH 
is not a reliable measure of levothyroxine sodium tablets dose adequacy in patients with 
secondary or tertiary hypothyroidism and should not be used to monitor therapy. Use the serum 
free-T4 level to monitor adequacy of therapy in this patient population. Titrate levothyroxine 
sodium tablets dosing per above instructions until the patient is clinically euthyroid and the 
serum free-T4 level is restored to the upper half of the normal range. 
Pediatric Dosage - Congenital or Acquired Hypothyroidism 
The recommended daily dose of levothyroxine sodium tablets in pediatric patients with 
hypothyroidism is based on body weight and changes with age as described in Table 1. Start 
levothyroxine sodium tablets at the full daily dose in most pediatric patients. Start at a lower 
starting dose in newborns (0-3 months) at risk for cardiac failure and in children at risk for 
hyperactivity (see below). Monitor for clinical and laboratory response [see Dosage and 
Administration (2.4)]. 
TABLE 1. LEVOTHYROXINE SODIUM TABLETS DOSING GUIDELINES 
FOR PEDIATRIC HYPOTHYROIDISM 
AGE 
Daily Dose Per Kg Body Weight 
a 
0-3 months 
10-15 mcg/kg/day 
3-6 months 
8-10 mcg/kg/day 
6-12 months 
6-8 mcg/kg/day 
1-5 years 
5-6 mcg/kg/day 
6-12 years 
4-5 mcg/kg/day 
Greater than 12 years but growth and puberty 
incomplete 
2-3 mcg/kg/day 
Growth and puberty complete 
1.6 mcg/kg/day 
a. The dose should be adjusted based on clinical response and laboratory 
parameters [see Dosage and Administration (2.4) and Use in Specific Populations 
(8.4)]. 
Newborns (0-3 months) at risk for cardiac failure: Consider a lower starting dose in newborns at 
risk for cardiac failure. Increase the dose every 4 to 6 weeks as needed based on clinical and 
laboratory response. 
Children at risk for hyperactivity: To minimize the risk of hyperactivity in children, start at one- 
fourth the 


153 
 
recommended full replacement dose, and increase on a weekly basis by one-fourth the full 
recommended replacement dose until the full recommended replacement dose is reached. 
Pregnancy 
Pre-existing Hypothyroidism: Levothyroxine sodium tablets dose requirements may increase 
during pregnancy. Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at 
minimum, during each trimester of pregnancy. In patients with primary hypothyroidism, maintain 
serum TSH in the trimester-specific reference range. For patients with serum TSH above the 
normal trimester-specific range, increase the dose of levothyroxine sodium tablets by 12.5 to 25 
mcg/day and measure TSH every 4 weeks until a stable levothyroxine sodium tablets dose is 
reached and serum TSH is within the normal trimester-specific range. Reduce levothyroxine 
sodium tablets dosage to pre-pregnancy levels immediately after delivery and measure serum 
TSH levels 4 to 8 weeks postpartum to ensure levothyroxine sodium tablets dose is 
appropriate. 
New Onset Hypothyroidism: Normalize thyroid function as rapidly as possible. In patients with 
moderate to severe signs and symptoms of hypothyroidism, start levothyroxine sodium tablets 
at the full replacement dose (1.6 mcg per kg body weight per day). In patients with mild 
hypothyroidism (TSH <10 
IU per liter) start levothyroxine sodium tablets at 1.0 mcg per kg body weight per day. 
Evaluate serum TSH every 4 weeks and adjust levothyroxine sodium tablets dosage until a 
serum TSH is within the normal trimester specific range [see Use in Specific Populations (8.1)]. 
TSH Suppression in Well-differentiated Thyroid Cancer  
Generally, TSH is suppressed to below 0.1 IU per liter, and this usually requires a levothyroxine 
sodium tablets dose of greater than 2 mcg per kg per day. However, in patients with high-risk 
tumors, the target level for TSH suppression may be lower.  
2.4 Monitoring TSH and/or Thyroxine (T4) Levels 
Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical 
evaluation. Persistent clinical and laboratory evidence of hypothyroidism despite an apparent 
adequate replacement dose of levothyroxine sodium tablets may be evidence of inadequate 
absorption, poor compliance, drug interactions or a combination of these factors. 
Adults  
In adult patients with primary hypothyroidism, monitor serum TSH levels after an interval of 6 
to 8 weeks after any change in dose. In patients on a stable and appropriate replacement 
dose, evaluate clinical and biochemical response every 6 to 12 months and whenever there is 
a change in the patient’s clinical status.  
Pediatrics  
In patients with congenital hypothyroidism, assess the adequacy of replacement therapy by 
measuring both serum TSH and total or free-T4. Monitor TSH and total or free-T4 in children as 
follows: 2 and 4 weeks after the initiation of treatment, 2 weeks after any change in dosage, and 
then every 3 to 12 months thereafter following dose stabilization until growth is completed. Poor 
compliance or abnormal values may necessitate more frequent monitoring. Perform routine 
clinical examination, including assessment of development, mental and physical growth and 
bone maturation, at regular intervals. 
While the general aim of therapy is to normalize the serum TSH level, TSH may not normalize 
in some patients due to in utero hypothyroidism causing a resetting of pituitary-thyroid 
feedback. Failure of the serum T4 to increase into the upper half of the normal range within 2 
weeks of initiation of 
levothyroxine sodium tablets therapy and/or of the serum TSH to decrease below 20 IU per liter 
within 
 


154 
 
4 weeks may indicate the child is not receiving adequate therapy. Assess compliance, 
dose of medication administered and method of administration prior to increasing the dose 
of levothyroxine sodium tablets [see Warnings and Precautions (5.1) and Use in Specific 
Populations (8.4)]. 
Secondary and Tertiary Hypothyroidism  
Monitor serum free-T4 levels and maintain in the upper half of the normal range in these 
patients. 
3 DOSAGE FORMS AND STRENGTHS 
Levothyroxine Sodium Tablets, USP are available as follows: 
Tablet Strength 
Tablet Color/Shape 
Tablet Markings 
25 mcg 
Orange/Caplet 
“25” and “GG/331” 
50 mcg 
White/ Caplet 
“50” and “GG/332” 
75 mcg 
Violet/ Caplet 
“75” and “GG/333” 
88 mcg 
Olive Green/ Caplet 
“88” and “GG/334” 
100 mcg 
Yellow/ Caplet 
“100” and “GG/335” 
112 mcg 
Rose/ Caplet 
“112” and “GG/336” 
125 mcg 
Brown/ Caplet 
“125” and “GG/337” 
137 mcg 
Turquoise/ Caplet 
“137” and “GG/330” 
150 mcg 
Blue/ Caplet 
“150” and “GG/338” 
175 mcg 
Lilac/ Caplet 
“175” and “GG/339” 
200 mcg 
Pink/ Caplet 
“200” and “GG/340” 
300 mcg 
Green/ Caplet 
“300” and “GG/341” 
4 CONTRAINDICATIONS 
Levothyroxine sodium tablets is contraindicated in patients with uncorrected adrenal 
insufficiency [see Warnings and Precautions (5.3)]. 
5 WARNINGS AND PRECAUTIONS 
5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying 
Cardiovascular Disease 
Over-treatment with levothyroxine may cause an increase in heart rate, cardiac wall thickness, 
and cardiac contractility and may precipitate angina or arrhythmias, particularly in patients with 
cardiovascular disease and in elderly patients. Initiate levothyroxine sodium tablets therapy in 
this population at lower doses than those recommended in younger individuals or in patients 
without cardiac disease [see Dosage and Administration (2.3), Use in Specific Populations (8.5)]. 


155 
 
Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery 
disease receiving suppressive levothyroxine sodium tablets therapy. Monitor patients receiving 
concomitant levothyroxine sodium tablets and sympathomimetic agents for signs and 
symptoms of coronary insufficiency. 
If cardiac symptoms develop or worsen, reduce the levothyroxine sodium tablets dose or 
withhold for one week and restart at a lower dose. 
5.2 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. Use of oral thyroid hormone drug products is not recommended to treat 
myxedema coma. Administer thyroid hormone products formulated for intravenous 
administration to treat myxedema coma. 
5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency 
Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid 
hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute adrenal 
crisis in patients with adrenal insufficiency. Treat patients with adrenal insufficiency with 
replacement glucocorticoids prior to initiating treatment with levothyroxine sodium tablets [see 
Contraindications (4)]. 
5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism 
Levothyroxine sodium tablets has a narrow therapeutic index. Over- or undertreatment with 
levothyroxine sodium tablets may have negative effects on growth and development, 
cardiovascular function, bone metabolism, reproductive function, cognitive function, 
emotional state, gastrointestinal function and glucose and lipid metabolism. Titrate the dose 
of levothyroxine sodium tablets carefully and monitor response to titration to avoid these 
effects [see Dosage and Administration (2.4)]. Monitor for the presence of drug or food 
interactions when using levothyroxine sodium tablets and adjust the dose as necessary [see 
Drug Interactions (7.9) and Clinical Pharmacology (12.3)]. 
5.5 Worsening of Diabetic Control 
Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic 
control and result in increased antidiabetic agent or insulin requirements. Carefully monitor 
glycemic control after starting, changing or discontinuing levothyroxine sodium tablets [see 
Drug Interactions (7.2)]. 
5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-
Replacement 
Increased bone resorption and decreased bone mineral density may occur as a result of 
levothyroxine over-replacement, particularly in post-menopausal women. 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. Administer the minimum dose of levothyroxine sodium tablets that achieves the 
desired clinical and biochemical response to mitigate this risk. 


156 
 
6 ADVERSE REACTIONS 
Adverse reactions associated with levothyroxine sodium tablets therapy are primarily those of 
hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5), Overdosage 
(10)]. 
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, muscle spasm  
• Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, 
heart failure, angina, myocardial infarction, cardiac arrest  
• Respiratory: dyspnea  
• Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests  
• Dermatologic: hair loss, flushing, rash  
• Endocrine: decreased bone mineral density  
• Reproductive: menstrual irregularities, impaired fertility 
Seizures have been reported rarely with the institution of levothyroxine therapy. 
ADVERSE REACTIONS IN CHILDREN 
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. 
HYPERSENSITIVITY REACTIONS 
Hypersensitivity reactions to inactive ingredients have occurred in patients treated with 
thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, 
angioedema, various gastrointestinal symptoms (abdominal pain, nausea, vomiting and 
diarrhea), fever, arthralgia, serum sickness and wheezing. Hypersensitivity to 
levothyroxine itself is not known to occur. 
7 DRUG INTERACTIONS 
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics 
Many drugs can exert effects on thyroid hormone pharmacokinetics and metabolism (e.g., 
absorption, synthesis, secretion, catabolism, protein binding and target tissue response) and 
may alter the therapeutic response to levothyroxine sodium tablets (see Tables 2-5 below). 
TABLE 2. DRUGS THAT MAY DECREASE T4 ABSORPTION (HYPOTHYROIDISM) 
Potential impact: Concurrent use may reduce the efficacy of levothyroxine sodium tablets 
by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. 


157 
 
Drug or Drug 
Class 
Effect 
Calcium 
Carbonate 
Ferrous Sulfate 
Calcium carbonate may form an insoluble chelate with levothyroxine, 
and ferrous sulfate likely forms a ferric- thyroxine complex. Administer 
levothyroxine sodium tablets at least 4 hours apart from these agents. 
Orlistat 
Monitor patients treated concomitantly with orlistat and levothyroxine 
sodium tablets for changes in thyroid function. 
Bile Acid 
Sequestrants  
-Colesevelam  
- 
Cholestyramine 
-Colestipol  
Ion Exchange 
Resins  
-Kayexalate  
-Sevelamer 
Bile acid sequestrants and ion exchange resins are known to decrease 
levothyroxine absorption. Administer levothyroxine sodium tablets at least 
4 hours prior to these drugs or monitor TSH levels. 
Other drugs: 
Proton Pump 
Inhibitors 
Sucralfate 
Antacids 
Aluminum 
&Magnesium 
Hydroxides 
Simethicone 
Gastric acidity is an essential requirement for adequate absorption of 
levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause 
hypochlorhydria, affect intragastric pH and reduce levothyroxine 
absorption. Monitor patients appropriately. 
TABLE 3. DRUGS THAT MAY ALTER T4 AND TRIIODOTHYRONINE (T3) SERUM TRANSPORT 
WITHOUT AFFECTING FREE THYROXINE (FT4) CONCENTRATION (EUTHYROIDISM) 
Drug or Drug Class 
Effect 
Clofibrate 
Estrogencontaining 
oral contraceptives 
Estrogens (oral) 
Heroin / 
Methadone 
5Fluorouracil 
Mitotane 
Tamoxifen 
These drugs may increase serum thyroxine-binding globulin 
(TBG) concentration. 


158 
 
Androgens / 
Anabolic 
Steroids 
Asparaginase  
Glucocorticoids 
Slow-Release 
Nicotinic Acid 
These drugs may decrease serum TBG concentration. 
Potential impact (below): Administration of these agents with levothyroxine 
sodium tablets results in an initial transient increase in FT4. Continued 
administration results in a decrease in serum T4 and normal FT4 and TSH 
concentrations. 
Salicylates (>2 
g/day) 
Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An 
initial increase in serum FT4 is followed by return of FT4 to normal 
levels with sustained therapeutic serum salicylate concentrations, 
although total T4 levels may decrease by as much as 30%. 
Other drugs: 
Carbamazepine 
Furosemide 
(>80 mg IV) 
Heparin  
Hydantoins  
Non-Steroidal 
Antiinflammatory 
Drugs  
-Fenamates 
These drugs may cause protein-binding site displacement. 
Furosemide has been shown to inhibit the protein binding of T4 to 
TBG and albumin, causing an increase free T4 fraction in serum. 
Furosemide competes for T4-binding sites on TBG, prealbumin and 
albumin, so that a single high dose can acutely lower the total T4 
level. Phenytoin and carbamazepine reduce serum protein binding 
of levothyroxine, and total and free T4 may be reduced by 20% to 
40%, but most patients have normal serum TSH levels and are 
clinically euthyroid. Closely monitor thyroid hormone parameters. 
TABLE 4. DRUGS THAT MAY ALTER HEPATIC METABOLISM OF T4 (HYPOTHYROIDISM) 
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme 
activity may cause increased hepatic degradation of levothyroxine, resulting in 
increased levothyroxine sodium tablets requirements. 
Drug or 
Drug Class 
Effect 
Phenobarbital 
Rifampin 
Phenobarbital has been shown to reduce the response to thyroxine. 
Phenobarbital increases L-thyroxine metabolism by inducing uridine 
5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 
serum levels. Changes in thyroid status may occur if barbiturates are 
added or withdrawn from patients being treated for hypothyroidism. 
Rifampin has been shown to accelerate the metabolism of 
levothyroxine. 


159 
 
TABLE 5. DRUGS THAT MAY DECREASE CONVERSION OF T4 TO T3 
Potential impact: 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. 
Drug or Drug Class Effect 
Beta-adrenergic 
antagonists (e.g., 
Propranolol 
>160 mg/day) 
In patients treated with large doses of propranolol (>160 mg/day), 
T3 and T4 levels change, TSH levels remain normal and patients 
are clinically euthyroid. Actions of particular betaadrenergic 
antagonists may be impaired when a hypothyroid patient is 
converted to the euthyroid state. 
Glucocorticoids 
(e.g., 
Dexamethasone 
≥4 mg/day) 
Short-term administration of large doses of glucocorticoids may 
decrease serum T3 concentrations by 30% with minimal change in 
serum T4 levels. However, long-term glucocorticoid therapy may 
result in slightly decreased T3 and T4 levels due to decreased TBG 
production (See above). 
Other drugs: 
Amiodarone 
Amiodarone inhibits peripheral conversion of levothyroxine (T4) to 
triiodothyronine (T3) and may cause isolated biochemical changes 
(increase in serum free-T4 and decreased or normal free-T3) in 
clinically euthyroid patients. 
7.2 Antidiabetic Therapy 
Addition of levothyroxine sodium tablets therapy in patients with diabetes mellitus may 
worsen glycemic control and result in increased antidiabetic agent or insulin requirements. 
Carefully monitor glycemic control, especially when thyroid therapy is started, changed or 
discontinued [see Warnings and Precautions (5.5)]. 
7.3 Oral Anticoagulants 
Levothyroxine sodium tablets 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 levothyroxine sodium tablets dose is increased. Closely monitor coagulation 
tests to permit appropriate and timely dosage adjustments. 
7.4 Digitalis Glycosides 
Levothyroxine sodium tablets may reduce the therapeutic effects of digitalis glycosides. Serum 
digitalis glycoside levels may decrease when a hypothyroid patient becomes euthyroid, 
necessitating an increase in the dose of digitalis glycosides. 
7.5 Antidepressant Therapy 
Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants 
and levothyroxine sodium tablets 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 central nervous system stimulation. Levothyroxine 
sodium tablets may accelerate the onset of action of tricyclics. Administration of sertraline in 


160 
 
patients stabilized on levothyroxine sodium tablets may result in increased levothyroxine 
sodium tablets requirements. 
7.6 Ketamine 
Concurrent use of ketamine and levothyroxine sodium tablets may produce marked 
hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients. 
7.7 Sympathomimetics 
Concurrent use of sympathomimetics and levothyroxine sodium tablets 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. 
7.8 Tyrosine-Kinase Inhibitors 
Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. 
Closely monitor TSH levels in such patients. 
7.9 Drug-Food Interactions 
Consumption of certain foods may affect levothyroxine sodium tablets absorption thereby 
necessitating adjustments in dosing [see Dosage and Administration (2.1)]. Soybean flour, 
cottonseed meal, walnuts and dietary fiber may bind and decrease the absorption of 
levothyroxine sodium tablets from the gastrointestinal tract. Grapefruit juice may delay the 
absorption of levothyroxine and reduce its bioavailability. 
7.10 Drug-Laboratory Test Interactions 
Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and 
evaluate unbound (free) hormone and/or determine the free-T4 index (FT4I) in this 
circumstance. Pregnancy, infectious hepatitis, estrogens, estrogen-containing oral 
contraceptives, and acute intermittent porphyria increase TBG concentration. Nephrosis, severe 
hypoproteinemia, severe liver disease, acromegaly, androgens and corticosteroids decrease 
TBG concentration. Familial hyper- or hypo-thyroxine binding globulinemias have been 
described, with the incidence of TBG deficiency approximating 1 in 9000. 
8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
Risk Summary 
Experience with levothyroxine use in pregnant women, including data from post-marketing 
studies, have not reported increased rates of major birth defects or miscarriages [see Data]. 
There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy. 
Since TSH levels may increase during pregnancy, TSH should be monitored and levothyroxine 
sodium tablets dosage adjusted during pregnancy [see Clinical Considerations]. There are no 
animal studies conducted with levothyroxine during pregnancy. Levothyroxine sodium tablets 
should not be discontinued during pregnancy and hypothyroidism diagnosed during pregnancy 
should be promptly treated. 
The estimated background risk of major birth defects and miscarriage for the indicated 
population is unknown. In the U.S. general population, the estimated background risk of 


161 
 
major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 
to 20%, respectively. 
Clinical Considerations 
Disease-Associated Maternal and/or Embryo/Fetal Risk 
Maternal hypothyroidism during pregnancy is associated with a higher rate of complications, 
including spontaneous abortion, gestational hypertension, pre-eclampsia, stillbirth and 
premature delivery. Untreated maternal hypothyroidism may have an adverse effect on fetal 
neurocognitive development. 
Dose Adjustments During Pregnancy and the Postpartum Period 
Pregnancy may increase levothyroxine sodium tablets requirements. Serum TSH levels should 
be monitored and the levothyroxine sodium tablets dosage adjusted during pregnancy. Since 
postpartum TSH levels are similar to preconception values, the levothyroxine sodium tablets 
dosage should return to the pre-pregnancy dose immediately after delivery [see Dosage and 
Administration (2.3)]. Data 
Human Data 
Levothyroxine is approved for use as a replacement therapy for hypothyroidism. There is a long 
experience of levothyroxine use in pregnant women, including data from post-marketing studies 
that have not reported increased rates of fetal malformations, miscarriages or other adverse 
maternal or fetal outcomes associated with levothyroxine use in pregnant women. 
Lactation 
Risk Summary 
Limited published studies report that levothyroxine is present in human milk. However, there 
is insufficient information to determine the effects of Levothyroxine on the breastfed infant and 
no available information on the effects of levothyroxine on milk production. Adequate 
levothyroxine treatment during lactation may normalize milk production in hypothyroid 
lactating mothers. The developmental and health benefits of breastfeeding should be 
considered along with the mother’s clinical need for levothyroxine sodium tablets and any 
potential adverse effects on the breastfed infant from levothyroxine sodium tablets or from the 
underlying maternal condition. 
Pediatric Use 
The initial dose of levothyroxine sodium tablets varies with age and body weight. Dosing 
adjustments are based on an assessment of the individual patient's clinical and laboratory 
parameters [see Dosage and Administration (2.3, 2.4)]. 
In children in whom a diagnosis of permanent hypothyroidism has not been established, 
discontinue levothyroxine sodium tablets administration for a trial period, but only after the child 
is at least 3 years of age. Obtain serum T4 and TSH levels at the end of the trial period, and 
use laboratory test results and clinical assessment to guide diagnosis and treatment, if 
warranted. 
6.2 Congenital Hypothyroidism [See Dosage and Administration (2.3, 2.4)] 
Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse 
effects of congenital hypothyroidism on intellectual development as well as on overall physical 


162 
 
growth and maturation. Therefore, initiate levothyroxine sodium tablets therapy immediately 
upon diagnosis. Levothyroxine is generally continued for life in these patients. 
Closely monitor infants during the first 2 weeks of levothyroxine sodium tablets therapy for 
cardiac overload, arrhythmias and aspiration from avid suckling. 
Closely monitor patients to avoid undertreatment or overtreatment. Undertreatment may have 
deleterious effects on intellectual development and linear growth. Overtreatment is associated 
with craniosynostosis in infants, may adversely affect the tempo of brain maturation and may 
accelerate the bone age and result in premature epiphyseal closure and compromised adult 
stature. 
Acquired Hypothyroidism in Pediatric Patients 
Closely monitor patients to avoid undertreatment and overtreatment. Undertreatment may result 
in poor school performance due to impaired concentration and slowed mentation and in 
reduced adult height. Overtreatment may accelerate the bone age and result in premature 
epiphyseal closure and compromised adult stature. 
Treated children may manifest a period of catch-up growth, which may be adequate in some 
cases to normalize adult height. In children with severe or prolonged hypothyroidism, catch-up 
growth may not be adequate to normalize adult height. 
Geriatric Use 
Because of the increased prevalence of cardiovascular disease among the elderly, initiate 
levothyroxine sodium tablets at less than the full replacement dose [see Warnings and Precautions 
(5.1) and Dosage and Administration (2.3)]. Atrial arrhythmias can occur in elderly patients. Atrial 
fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in 
the elderly. 
10 OVERDOSAGE 
The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and 
Precautions (5) and Adverse Reactions (6)]. In addition, confusion and disorientation may occur. 
Cerebral embolism, shock, coma and death have been reported. Seizures occurred in a 3-year- 
old child ingesting 3.6 mg of levothyroxine. Symptoms may not necessarily be evident or may 
not appear until several days after ingestion of levothyroxine sodium. 
Reduce the levothyroxine sodium tablets dose or discontinue temporarily if signs or symptoms 
of overdosage occur. Initiate appropriate supportive treatment as dictated by the patient’s 
medical status. 
For current information on the management of poisoning or overdosage, contact the National 
Poison Control Center at 1-800-222-1222 or www.poison.org. 
11 DESCRIPTION 
Levothyroxine sodium tablets, USP contain synthetic crystalline L-3,3',5,5'- tetraiodothyronine 
sodium salt [levothyroxine (T4) sodium]. Synthetic T4 is chemically identical to that produced in 
the human thyroid gland. Levothyroxine (T4) sodium has an empirical formula of 
C15H10I4NNaO4 •xH2O (where x = 5), molecular weight of 798.86 g/mol (anhydrous) and 
structural formula as shown: 


163 
 
 
Levothyroxine sodium tablets for oral administration are supplied in the following strengths: 25 
mcg, 50 mcg, 75 mcg, 88 mcg, 100 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 
mcg and 300 mcg. 
Each levothyroxine sodium tablet contains the inactive ingredients Magnesium Stearate, NF; 
Microcrystalline Cellulose, NF; Colloidal Silicone Dioxide, NF; and Sodium Starch Glycolate, 
NF. Each tablet strength meets USP Dissolution Test 2. Table 6 provides a listing of the color 
additives by tablet strength: 
TABLE 6. LEVOTHYROXINE SODIUM TABLETS COLOR ADDITIVES 
Strength 
(mcg) 
Color additive(s) 
25 
FD&C Yellow No. 6 Aluminum Lake 
50 
None 
75 
FD&C Blue No. 2 Aluminum Lake, D&C Red No. 27 Aluminum Lake 
88 
FD&C Blue No. 1 Aluminum Lake, D&C Yellow No. 10 Aluminum 
Lake, D&C RedNo. 30 Aluminum Lake 
100 
D&C Yellow No. 10 Aluminum Lake, D&C Red Lake Blend (D&C Red 
No. 27 Lake and D&C Red No. 30 Lake) 
112 
D&C Red No. 27 Aluminum Lake, D&C Red No. 30 Aluminum Lake 
125 
FD&C Yellow No. 6 Aluminum Lake, FD&C Red No. 40 Aluminum 
Lake, FD&C Blue No. 1 Aluminum Lake 
137 
FD&C Blue No. 1 Aluminum Lake 
150 
FD&C Blue No. 2 Aluminum Lake 
175 
D&C Red No. 27 Aluminum Lake, D&C Red No. 30 Aluminum Lake, 
FD&C Blue No. 1 Aluminum Lake 
200 
D&C Yellow No. 10 Aluminum Lake, D&C Red No. 27 Aluminum Lake 
300 
D&C Yellow No. 10 Aluminum Lake, FD&C Yellow No. 6 Aluminum 
Lake, FD&C Blue No. 1 Aluminum Lake 
 
 


164 
 
CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
Thyroid hormones exert their physiologic actions through control of DNA transcription and 
protein synthesis. Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell nucleus and 
bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor complex 
activates gene transcription and synthesis of messenger RNA and cytoplasmic proteins. 
The physiological actions of thyroid hormones are produced predominantly by T3, the majority 
of which (approximately 80%) is derived from T4 by deiodination in peripheral tissues. 
12.2 Pharmacodynamics 
Oral levothyroxine sodium is a synthetic T4 hormone that exerts the same physiologic effect as 
endogenous T4, thereby maintaining normal T4 levels when a deficiency is present. 
12.3 Pharmacokinetics 
Absorption 
Absorption of orally administered T4 from the gastrointestinal tract ranges from 40% to 80%. 
The majority of the levothyroxine sodium tablets dose is absorbed from the jejunum and upper 
ileum. The relative bioavailability of levothyroxine sodium tablets, compared to an equal 
nominal dose of oral levothyroxine sodium solution, is approximately 99%. T4 absorption is 
increased by fasting, and decreased in malabsorption syndromes and by certain foods such 
as soybeans. Dietary fiber decreases bioavailability of T4. Absorption may also decrease with 
age. In addition, many drugs and foods affect T4 absorption [see Drug Interactions (7)]. 
Distribution 
Circulating thyroid hormones are greater than 99% bound to plasma proteins, including 
thyroxinebinding globulin (TBG), thyroxine-binding prealbumin (TBPA) and albumin (TBA), 
whose capacities and affinities vary for each hormone. The higher affinity of both TBG and 
TBPA for T4 partially explains the higher serum levels, slower metabolic clearance and longer 
half-life of T4 compared to T3. Protein-bound thyroid hormones exist in reverse equilibrium 
with small amounts of free hormone. Only unbound hormone is metabolically active. Many 
drugs and physiologic conditions affect the binding of thyroid hormones to serum proteins [see 
Drug Interactions (7)]. Thyroid hormones do not readily cross the placental barrier [see Use in 
Specific Populations (8.1)]. 
Elimination 
Metabolism 
T4 is slowly eliminated (see Table 7). The major pathway of thyroid hormone metabolism is 
through sequential deiodination. Approximately 80% of circulating T3 is derived from peripheral 
T4 by monodeiodination. The liver is the major site of degradation for both T4 and T3, with T4 
deiodination also occurring at a number of additional sites, including the kidney and other 
tissues. Approximately 80% of the daily dose of T4 is deiodinated to yield equal amounts of T3 
and reverse T3 (rT3). T3 and rT3 are further deiodinated to diiodothyronine. Thyroid hormones 
are also metabolized via conjugation with glucuronides and sulfates and excreted directly into 
the bile and gut where they undergo enterohepatic recirculation. 
Excretion 


165 
 
Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated 
hormone reaches the colon unchanged and is eliminated in the feces. Approximately 20% of 
T4 is eliminated in the stool. Urinary excretion of T4 decreases with age. 
TABLE 7. PHARMACOKINETIC PARAMETERS OF THYROID HORMONES IN EUTHYROID   
PATIENTS 
Hormone 
Ratio in 
Thyroglobulin 
Biologic 
Potency 
t 1/2 
(days) 
Protein 
Binding 
(%) a 
Levothyroxine 
(T4) 
10 - 20 
1 
6-7 b 
99.96 
Liothyronine 
(T3) 
1 
4 
≤ 2 
99.5 
a. Includes TBG, TBPA and TBA  
b. 3 to 4 days in hyperthyroidism, 9 to 10 days in 
hypothyroidism 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
Standard animal studies have not been performed to evaluate the carcinogenic potential, 
mutagenic potential or effects on fertility of levothyroxine. 
16 HOW SUPPLIED/STORAGE AND HANDLING 
Levothyroxine Sodium Tablets, USP are supplied as follows: 
Strength 
(mcg) 
Color/Shape 
Tablet 
Markings 
NDC# for 
bottles of 90 
NDC # for bottles of 
1000 
25 
Orange/Caplet “25” and 
“GG/331” 
0781-5180-92 
0781-5180-10 
50 
White/ Caplet “50” and 
“GG/332” 
0781-5181-92 
0781-5181-10 
75 
Violet/ Caplet “75” and 
“GG/333” 
0781-5182-92 
0781-5182-10 
88 
Olive Green/ 
Caplet 
“88” and 
‘GG/334” 
0781-5183-92 
0781-5183-10 
100 
Yellow/ Caplet “100” and 
“GG/335” 
0781-5184-92 
0781-5184-10 
 


166 
 
112 
Rose/ Caplet 
“112” and 
“GG/336” 
0781-5185-92 
0781-5185-10 
125 
Brown/ Caplet “125” and 
“GG/337” 
0781-5186-92 
0781-5186-10 
137 
Turquoise/ 
Caplet 
“137” and 
“GG/330” 
0781-5191-92 
0781-5191-10 
150 
Blue/ Caplet 
“150” and 
“GG/338” 
0781-5187-92 
0781-5187-10 
175 
Lilac/ Caplet 
“175” and 
“GG/339” 
0781-5188-92 
0781-5188-10 
200 
Pink/ Caplet 
“200” and 
“GG/340” 
0781-5189-92 
0781-5189-10 
300 
Green/ Caplet “300” and 
“GG/341” 
0781-5190-92 
0781-5190-10 
STORAGE CONDITIONS 
Store at 25°C (77°F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled 
Room Temperature]. Levothyroxine sodium tablets should be protected from light and moisture. 
17 PATIENT COUNSELING INFORMATION 
Inform the patient of the following information to aid in the safe and effective use of levothyroxine 
sodium tablets: 
Dosing and Administration 
• Instruct patients that levothyroxine sodium tablets should be taken with a full glass of water 
since thetablet may rapidly disintegrate.  
• Instruct patients to take levothyroxine sodium tablets only as directed by their healthcare 
provider.  
• Instruct patients to take levothyroxine sodium tablets as a single dose, preferably on an empty 
stomach,one-half to one hour before breakfast.  
• Inform patients that agents such as iron and calcium supplements and antacids can decrease 
theabsorption of levothyroxine. Instruct patients not to take levothyroxine sodium tablets within 
4 hours of these agents.  
• Instruct patients to notify their healthcare provider if they are pregnant or breastfeeding or are 
thinkingof becoming pregnant while taking levothyroxine sodium tablets. 
Important Information 
• Inform patients that it may take several weeks before they notice an improvement in symptoms.  
• Inform patients that the levothyroxine in levothyroxine sodium tablets is intended to replace a 
hormonethat is normally produced by the thyroid gland. Generally, replacement therapy is to be 
taken for life.  
• Inform patients that levothyroxine sodium tablets should not be used as a primary or adjunctive 
therapyin a weight control program.  


167 
 
• Instruct patients to notify their healthcare provider if they are taking any other medications, 
includingprescription and over-the-counter preparations.  
• Instruct patients to notify their physician of any other medical conditions they may have, 
particularlyheart disease, diabetes, clotting disorders and adrenal or pituitary gland problems, 
as the dose of medications used to control these other conditions may need to be adjusted 
while they are taking levothyroxine sodium tablets. If they have diabetes, instruct patients to 
monitor their blood and/or urinary glucose levels as directed by their physician and immediately 
report any changes to their physician. If patients are taking anticoagulants, their clotting status 
should be checked frequently.  
• Instruct patients to notify their physician or dentist that they are taking levothyroxine sodium 
tabletsprior to any surgery. Adverse Reactions 
• Instruct patients to notify their healthcare provider if they experience any of the following 
symptoms: 
rapid or irregular heartbeat, chest pain, shortness of breath, leg cramps, headache, 
nervousness, irritability, sleeplessness, tremors, change in appetite, weight gain or loss, 
vomiting, diarrhea, excessive sweating, heat intolerance, fever, changes in menstrual 
periods, hives or skin rash or any other unusual medical event.  
• Inform patients that partial hair loss may occur rarely during the first few months of 
levothyroxinesodium tablets therapy, but this is usually temporary. 
 


168 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


169 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0781-5183 
Route of Administration 
ORAL 
 


170 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) 
(LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 LEVOTHYROXINE SODIUM 
ANHYDROUS 
88 ug 
 
 
Inactive Ingredients 
 
 
Ingredient Name 
 
Strength 
FD&C BLUE NO. 1--ALUMINUM LAKE (UNII: J9EQA3S2JM) 
 
  
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) 
 
  
D&C RED NO. 30 (UNII: 2S42T2808B) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) 
 
  
 
 
Product Characteristics 
 
Color 
green (olive green) 
Score 
2 pieces 
Shape 
CAPSULE 
Size 
9mm 
Flavor 
 
Imprint Code 
88;GG;334 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start Date 
 Marketing End Date 
1 NDC:0781-5183-92 90 in 1 BOTTLE; Type 0: Not a Combination Product 
04/16/2012 
  
2 NDC:0781-5183-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 
03/01/2002 
  
 
 


171 
 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
 Marketing End Date 
NDA authorized generic 
NDA021342 
03/01/2002 
  
 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0781-5184 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
D&C RED NO. 30 (UNII: 2S42T2808B) 
 
D&C RED NO. 27 (UNII: 2LRS185U6K) 
 
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) 
 
 
 
 
 
 
 
 
 


172 
 
 
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) 
 
  
 
 
Product Characteristics 
 
Color 
yellow 
Score 
 
2 pieces 
Shape 
CAPSULE 
Size 
 
9mm 
Flavor 
 
Imprint Code 
 
100;GG;335 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:0781-5184-92 90 in 1 BOTTLE; Type 0: Not a Combination Product 
04/16/2012 
 
2 NDC:0781-5184-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 
03/01/2002 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
NDA authorized generic 
NDA021342 
03/01/2002 
 
 
 


173 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0781-5185 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
112 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
D&C RED NO. 27 ALUMINUM LAKE (UNII: ZK64F7XSTX) 
 
  
D&C RED NO. 30 (UNII: 2S42T2808B) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) 
 
  
 


174 
 
 
 
Product Characteristics 
 
Color 
red (rose) 
Score 
 
2 pieces 
Shape 
CAPSULE 
Size 
 
9mm 
Flavor 
 
Imprint Code 
 
112;GG;336 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:0781-5185-92 90 in 1 BOTTLE; Type 0: Not a Combination Product 
04/16/2012 
 
2 NDC:0781-5185-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 
03/01/2002 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
NDA authorized generic 
NDA021342 
03/01/2002 
 
 
 


175 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0781-5186 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
125 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
FD&C RED NO. 40 (UNII: WZB9127XOA) 
 
  
FD&C YELLOW NO. 6 (UNII: H77VEI93A8) 
 
  
FD&C BLUE NO. 1--ALUMINUM LAKE (UNII: J9EQA3S2JM) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) 
 
  
 
 
Product Characteristics 
 
Color 
brown 
Score 
 
2 pieces 
Shape 
CAPSULE 
Size 
 
9mm 


176 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Flavor 
 
Imprint Code 
 
125;GG;337 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:0781-5186-92 90 in 1 BOTTLE; Type 0: Not a Combination Product 
04/16/2012 
 
2 NDC:0781-5186-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 
03/01/2002 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
NDA authorized generic 
NDA021342 
03/01/2002 
 
 
 


177 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


178 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:0781-5191-92 90 in 1 BOTTLE; Type 0: Not a Combination Product 
04/16/2012 
 
2 NDC:0781-5191-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 
03/01/2002 
 
 
 
 
Marketing Information 
 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
NDA authorized generic 
NDA021342 
03/01/2002 
 
 
 
 


179 
 
 
 
 
 
 
 


180 
 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0781-5188 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
175 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
D&C RED NO. 27 ALUMINUM LAKE (UNII: ZK64F7XSTX) 
 
  
D&C RED NO. 30 (UNII: 2S42T2808B) 
 
  
FD&C BLUE NO. 1--ALUMINUM LAKE (UNII: J9EQA3S2JM) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) 
 
  
 
 
 
 
 
Marketing Information 
 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
NDA authorized generic 
NDA021342 
03/01/2002 
 
 
 
 


181 
 
 
 
Product Characteristics 
 
Color 
purple (lilac) 
Score 
 
2 pieces 
Shape 
CAPSULE 
Size 
 
9mm 
Flavor 
 
Imprint Code 
 
175;GG;339 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:0781-5188-92 90 in 1 BOTTLE; Type 0: Not a Combination Product 
04/16/2012 
 
2 NDC:0781-5188-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 
03/01/2002 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
NDA authorized generic 
NDA021342 
03/01/2002 
 
 
 
 


182 
 
LEVOTHYROXINE SODIUM   


183 
 
 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0781-5189 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
200 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
D&C RED NO. 27 ALUMINUM LAKE (UNII: ZK64F7XSTX) 
 
  
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) 
 
  
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
 
 
Product Characteristics 
 
Color 
pink 
Score 
 
2 pieces 
levothyroxine sodium tablet 


184 
 
 
 
 
 
 
Shape 
CAPSULE 
Size 
 
9mm 
Flavor 
 
Imprint Code 
 
200;GG;340 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:0781-5189-92 90 in 1 BOTTLE; Type 0: Not a Combination Product 
04/16/2012 
 
2 NDC:0781-5189-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 
03/01/2002 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
NDA authorized generic 
NDA021342 
03/01/2002 
 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0781-5190 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
300 ug 
 
 


185 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
FD&C YELLOW NO. 6 (UNII: H77VEI93A8) 
 
  
D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) 
 
  
FD&C BLUE NO. 1--ALUMINUM LAKE (UNII: J9EQA3S2JM) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) 
 
  
 
 
Product Characteristics 
 
Color 
green 
Score 
 
2 pieces 
Shape 
CAPSULE 
Size 
 
9mm 
Flavor 
 
Imprint Code 
 
300;GG;341 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:0781-5190-92 90 in 1 BOTTLE; Type 0: Not a Combination Product 
04/16/2012 
 
2 NDC:0781-5190-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 
03/01/2002 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
NDA authorized generic 
NDA021342 
03/01/2002 
 
 
 


186 
 
 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
25 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
FD&C YELLOW NO. 6 (UNII: H77VEI93A8) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) 
 
  
 
 
Product Characteristics 
 
Color 
orange 
Score 
 
2 pieces 
Shape 
CAPSULE 
Size 
 
9mm 
Flavor 
 
Imprint Code 
 
25;GG;331 
Contains 
     
 
 
 
 
 
 
 
 
 
 
 
 


187 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:0781-5180-92 90 in 1 BOTTLE; Type 0: Not a Combination Product 
04/16/2012 
 
2 NDC:0781-5180-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 
03/01/2002 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
NDA authorized generic 
NDA021342 
03/01/2002 
 
 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0781-5181 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
50 ug 
 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  


188 
 
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) 
 
  
 
 
Product Characteristics 
 
Color 
white 
Score 
 
2 pieces 
Shape 
CAPSULE 
Size 
 
9mm 
Flavor 
 
Imprint Code 
 
50;GG;332 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:0781-5181-92 90 in 1 BOTTLE; Type 0: Not a Combination Product 
04/16/2012 
 
2 NDC:0781-5181-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 
03/01/2002 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
NDA authorized generic 
NDA021342 
03/01/2002 
 
 
 
LEVOTHYROXINE SODIUM   
levothyroxine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:0781-5182 
Route of Administration 
ORAL 


189 
 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
LEVOTHYROXINE SODIUM (UNII: 9J765S329G) (LEVOTHYROXINE - 
UNII:Q51BO43MG4) 
 
LEVOTHYROXINE SODIUM 
ANHYDROUS 
75 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
FD&C BLUE NO. 2--ALUMINUM LAKE (UNII: 4AQJ3LG584) 
 
  
D&C RED NO. 27 ALUMINUM LAKE (UNII: ZK64F7XSTX) 
 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
 
  
Labeler - Sandoz Inc. (110342024) 


190 
 
Registrant - Neolpharma, Inc. (078709787) 
Establishment 
 
Name 
Address 
ID/FEI 
Business Operations 
Neolpharma, 
Inc 
 
078709787 
manufacture(0781-5180, 0781-5181, 0781-5182, 0781-5184, 0781-5186, 0781-5187, 0781-5183, 
0781-5185, 0781-5191, 0781-5188, 0781-5189, 0781-5190) , analysis(0781-5180, 0781-5181, 
0781-5182, 0781-5184, 0781-5186, 0781-5187, 0781-5183, 0781-5185, 0781-5191, 0781-5188, 
0781-5189, 0781-5190) , pack(0781-5180, 0781-5181, 0781-5182, 0781-5184, 0781-5186, 0781- 
5187, 0781-5183, 0781-5185, 0781-5191, 0781-5188, 0781-5189, 0781-5190) , label(0781-5184, 
0781-5180, 0781-5181, 0781-5182, 0781-5186, 0781-5187, 0781-5183, 0781-5185, 0781-5191, 
0781-5188, 0781-5189, 0781-5190) 
Establishment 
Name 
Address 
ID/FEI 
Business Operations 
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) 
 
  
SILICON DIOXIDE (UNII: ETJ7Z6XBU4) 
 
  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) 
 
  
 
 
Product Characteristics 
 
Color 
purple (violet) 
Score 
 
2 pieces 
Shape 
CAPSULE 
Size 
 
9mm 
Flavor 
 
Imprint Code 
 
75;GG;333 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:0781-5182-92 90 in 1 BOTTLE; Type 0: Not a Combination Product 
04/16/2012 
 
2 NDC:0781-5182-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 
03/01/2002 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
NDA authorized generic 
NDA021342 
03/01/2002 
 
 
 


191 
 
theon 
Puerto 
Rico, 
Inc. 
 
143814544 
manufacture(0781-5188, 0781-5189, 0781-5190, 0781-5183, 0781-5184, 0781-5185, 0781-5186, 
07815191, 0781-5187, 0781-5180, 0781-5181, 0781-5182) , analysis(0781-5180, 0781-5181, 0781-5182, 
07815183, 0781-5184, 0781-5185, 0781-5186, 0781-5187, 0781-5188, 0781-5189, 0781-5190, 0781-
5191) , pack(0781-5180, 0781-5181, 0781-5182, 0781-5183, 0781-5184, 0781-5185, 0781-5186, 0781-
5187, 
0781-5188, 0781-5189, 0781-5190, 0781-5191) , label(0781-5180, 0781-5181, 0781-5182, 0781-5183, 
0781-5184, 0781-5185, 0781-5186, 0781-5187, 0781-5188, 0781-5189, 0781-5190, 0781-5191) 
Revised: 4/2019  
Sandoz Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


192 
 
APPENDIX E 
CYTOMEL® 
brand of liothyronine 
sodium tablets 
DESCRIPTION 
Thyroid hormone drugs are natural or synthetic preparations containing tetraiodothyronine (T4, 
levothyroxine) sodium or triiodothyronine (T3, liothyronine) sodium or both. T4 and T3 are 
produced in the human thyroid gland by the iodination and coupling of the amino acid tyrosine. 
T4 contains four iodine atoms and is formed by the coupling of two molecules of diiodotyrosine 
(DIT). T3 contains three atoms of iodine and is formed by the coupling of one molecule of DIT 
with one molecule of monoiodotyrosine (MIT). Both hormones are stored in the thyroid colloid 
as thyroglobulin. 
Thyroid hormone preparations belong to two categories: (1) natural hormonal preparations 
derived from animal thyroid, and (2) synthetic preparations. Natural preparations include 
desiccated thyroid and thyroglobulin. Desiccated thyroid is derived from domesticated animals 
that are used for food by man (either beef or hog thyroid), and thyroglobulin is derived from 
thyroid glands of the hog. The United States Pharmacopeia (USP) has standardized the total 
iodine content of natural preparations. Thyroid USP contains not less than (NLT) 0.17 percent 
and not more than (NMT) 0.23 percent iodine, and thyroglobulin contains not less than (NLT) 
0.7 percent of organically bound iodine. Iodine content is only an indirect indicator of true 
hormonal biologic activity. 
Cytomel (liothyronine sodium) Tablets contain liothyronine (L-triiodothyronine or L 
T3), a 
synthetic form of a natural thyroid hormone, and is available as the sodium salt. 


193 
 
The structural and empirical formulas and molecular weight of liothyronine sodium are given 
below. 
Liothyronine Sodium 
 
L-Tyrosine, O-(4-hydroxy-3-iodophenyl)-3,5-diiodo-, monosodium salt 
Twenty-five mcg of liothyronine is equivalent to approximately 1 grain of desiccated thyroid or 
thyroglobulin and 0.1 mg of L-thyroxine. 
Each round, white to off-white Cytomel (liothyronine sodium) tablet contains liothyronine sodium 
equivalent to liothyronine as follows: 5 mcg debossed JMI and D14; 25 mcg scored and 
debossed JMI and D16; 50 mcg scored and debossed JMI and D17. Inactive ingredients 
consist of calcium sulfate, gelatin, starch, stearic acid, sucrose and talc. 
CLINICAL PHARMACOLOGY 
The mechanisms by which thyroid hormones exert their physiologic action are not well 
understood. These hormones enhance oxygen consumption by most tissues of the body, 
increase the basal metabolic rate and the metabolism of carbohydrates, lipids and proteins. 
Thus, they exert a profound influence on every organ system in the body and are of particular 
importance in the development of the central nervous system. 
PHARMACOKINETICS 
Since liothyronine sodium (T3) is not firmly bound to serum protein, it is readily available to body 
tissues. The onset of activity of liothyronine sodium is rapid, occurring within a few hours. 
Maximum pharmacologic response occurs within 2 or 3 days, providing early clinical response. 
The biological half-life is about 2-1/2 days. 


194 
 
T3 is almost totally absorbed, 95 percent in 4 hours. The hormones contained in the 
natural preparations are absorbed in a manner similar to the synthetic hormones. 
Liothyronine sodium has a rapid cutoff of activity which permits quick dosage adjustment and 
facilitates control of the effects of overdosage, should they occur. 
The higher affinity of levothyroxine (T4) for both thyroid-binding globulin and thyroid-binding 
prealbumin as compared to triiodothyronine (T3) partially explains the higher serum levels and 
longer half-life of the former hormone. Both protein-bound hormones exist in reverse equilibrium 
with minute amounts of free hormone, the latter accounting for the metabolic activity. 
INDICATIONS AND USAGE 
Thyroid hormone drugs are indicated: 
1. As replacement or supplemental therapy in patients with hypothyroidism of any etiology, 
except transient hypothyroidism during the recovery phase of subacute thyroiditis. This 
category includes cretinism, myxedema and ordinary hypothyroidism in patients of any 
age (pediatric patients, adults, the elderly), or state (including pregnancy); primary 
hypothyroidism resulting from functional deficiency, primary atrophy, partial or total 
absence of thyroid gland, or the effects of surgery, radiation, or drugs, with or without 
the presence of goiter; and secondary (pituitary) or tertiary (hypothalamic) 
hypothyroidism (see WARNINGS). 
2. As pituitary thyroid-stimulating hormone (TSH) suppressants, in the treatment or 
prevention of various types of euthyroid goiters, including thyroid nodules, subacute or 
chronic lymphocytic thyroiditis (Hashimoto’s) and multinodular goiter. 
3. As diagnostic agents in suppression tests to differentiate suspected mild 
hyperthyroidism or thyroid gland autonomy. 


195 
 
Cytomel (liothyronine sodium) Tablets can be used in patients allergic to desiccated thyroid or 
thyroid extract derived from pork or beef. 
CONTRAINDICATIONS 
Thyroid hormone preparations are generally contraindicated in patients with diagnosed but as 
yet uncorrected adrenal cortical insufficiency, untreated thyrotoxicosis and apparent 
hypersensitivity to any of their active or extraneous constituents. There is no well-documented 
evidence from the literature, however, of true allergic or idiosyncratic reactions to thyroid 
hormone. 
WARNINGS 
Drugs with thyroid hormone activity, alone or together with other therapeutic agents, have 
been used for the treatment of obesity. 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. 
The use of thyroid hormones in the therapy of obesity, alone or combined with other drugs, is 
unjustified and has been shown to be ineffective. Neither is their use justified for the treatment 
of male or female infertility unless this condition is accompanied by hypothyroidism. 
Thyroid hormones should be used with great caution in a number of circumstances where the 
integrity of the cardiovascular system, particularly the coronary arteries, is suspected. These 
include patients with angina pectoris or the elderly, in whom there is a greater likelihood of 
occult cardiac disease. In these patients, liothyronine sodium therapy should be initiated with 
low doses, with due consideration for its relatively rapid onset of action. Starting dosage of 


196 
 
Cytomel (liothyronine sodium) Tablets is 5 mcg daily, and should be increased by no more than 
5 mcg increments at 2-week intervals. When, in such patients, a euthyroid state can only be 
reached at the expense of an aggravation of the cardiovascular disease, thyroid hormone 
dosage should be reduced. 
Morphologic hypogonadism and nephrosis should be ruled out before the drug is administered. 
If hypopituitarism is present, the adrenal deficiency must be corrected prior to starting the drug. 
Myxedematous patients are very sensitive to thyroid; dosage should be started at a very low 
level and increased gradually. 
Severe and prolonged hypothyroidism can lead to a decreased level of adrenocortical activity 
commensurate with the lowered metabolic state. When thyroid-replacement therapy is 
administered, the metabolism increases at a greater rate than adrenocortical activity. This can 
precipitate adrenocortical insufficiency. Therefore, in severe and prolonged hypothyroidism, 
supplemental adrenocortical steroids may be necessary. In rare instances the administration of 
thyroid hormone may precipitate a hyperthyroid state or may aggravate existing 
hyperthyroidism. 
PRECAUTIONS 
General – Thyroid hormone therapy in patients with concomitant diabetes mellitus or insipidus 
or adrenal cortical insufficiency aggravates the intensity of their symptoms. Appropriate 
adjustments of the various therapeutic measures directed at these concomitant endocrine 
diseases are required. 
The therapy of myxedema coma requires simultaneous administration of 
glucocorticoids. 
Hypothyroidism decreases and hyperthyroidism increases the sensitivity to oral anticoagulants. 
Prothrombin time should be closely monitored in thyroid-treated patients on oral anticoagulants 
and dosage of the latter agents adjusted on the basis of frequent prothrombin time 


197 
 
determinations. In infants, excessive doses of thyroid hormone preparations may produce 
craniosynostosis. 
Information for the Patient – Patients on thyroid hormone preparations and parents of 
pediatric patients on thyroid therapy should be informed that: 
1. Replacement therapy is to be taken essentially for life, with the exception of cases of 
transient hypothyroidism, usually associated with thyroiditis, and in those patients 
receiving a therapeutic trial of the drug. 
2. They should immediately report during the course of therapy any signs or symptoms of 
thyroid hormone toxicity, e.g., chest pain, increased pulse rate, palpitations, excessive 
sweating, heat intolerance, nervousness, or any other unusual event. 
3. In case of concomitant diabetes mellitus, the daily dosage of antidiabetic medication 
may need readjustment as thyroid hormone replacement is achieved. If thyroid 
medication is stopped, a downward readjustment of the dosage of insulin or oral 
hypoglycemic agent may be necessary to avoid hypoglycemia. At all times, close 
monitoring of urinary glucose levels is mandatory in such patients. 
4. In case of concomitant oral anticoagulant therapy, the prothrombin time should be 
measured frequently to determine if the dosage of oral anticoagulants is to be 
readjusted. 
5. Partial loss of hair may be experienced by pediatric patients in the first few months of 
thyroid therapy, but this is usually a transient phenomenon and later recovery is usually 
the rule. 
Laboratory Tests – Treatment of patients with thyroid hormones requires the periodic 
assessment of thyroid status by means of appropriate laboratory tests besides the full clinical 
evaluation. The TSH suppression test can be used to test the effectiveness of any thyroid 
preparation, bearing in mind the relative insensitivity of the infant pituitary to the negative 
feedback effect of thyroid hormones. Serum T4 levels can be used to test the effectiveness of 


198 
 
all thyroid medications except products containing liothyronine sodium. When the total serum 
T4 is low but TSH is normal, a test specific to assess unbound (free) T4 levels is warranted. 
Specific measurements of T4 and T3 by competitive protein binding or radioimmunoassay are 
not influenced by blood levels of organic or inorganic iodine and have essentially replaced older 
tests of thyroid hormone measurements, i.e., PBI, BEI and T4 by column. 
DRUG INTERACTIONS 
OralAnticoagulants – Thyroid hormones appear to increase catabolism of vitamin K-
dependent  
clotting factors. If oral anticoagulants are also being given, compensatory increases in clotting 
factor synthesis are impaired. Patients stabilized on oral anticoagulants who are found to 
require thyroid replacement therapy should be watched very closely when thyroid is started. If a 
patient is truly hypothyroid, it is likely that a reduction in anticoagulant dosage will be required. 
No special precautions appear to be necessary when oral anticoagulant therapy is begun in a 
patient already stabilized on maintenance thyroid replacement therapy. 
Insulin or Oral Hypoglycemics – Initiating thyroid replacement therapy may cause increases 
in insulin or oral hypoglycemic requirements. The effects seen are poorly understood and 
depend upon a variety of factors such as dose and type of thyroid preparations and 
endocrine status of the patient. Patients receiving insulin or oral hypoglycemics should be 
closely watched during initiation of thyroid replacement therapy. 
Cholestyramine – Cholestyramine binds both T4 and T3 in the intestine, thus impairing 
absorption of these thyroid hormones. In vitro studies indicate that the binding is not easily 


199 
 
removed. Therefore, 4 to 5 hours should elapse between administration of cholestyramine 
and thyroid hormones. 
Estrogen, Oral Contraceptives – Estrogens tend to increase serum thyroxine-binding 
globulin (TBg). In a patient with a nonfunctioning thyroid gland who is receiving thyroid 
replacement therapy, free levothyroxine may be decreased when estrogens are started 
thus increasing thyroid requirements. However, if the patient’s thyroid gland has sufficient 
function, the decreased free thyroxine will result in a compensatory increase in thyroxine 
output by the thyroid. Therefore, patients without a functioning thyroid gland who are on 
thyroid replacement therapy may need to increase their thyroid dose if estrogens 
or estrogen-containing oral contraceptives are given. 
Tricyclic Antidepressants – Use of thyroid products with imipramine and other tricyclic 
antidepressants may increase receptor sensitivity and enhance antidepressant activity; 
transient cardiac arrhythmias have been observed. Thyroid hormone activity may also be 
enhanced. 
Digitalis – Thyroid preparations may potentiate the toxic effects of digitalis. Thyroid 
hormonal replacement increases metabolic rate, which requires an increase in digitalis 
dosage. 
Ketamine – When administered to patients on a thyroid preparation, this parenteral 
anesthetic may cause hypertension and tachycardia. Use with caution and be prepared to 
treat hypertension, if necessary. 


200 
 
Vasopressors – Thyroxine increases the adrenergic effect of catecholamines such as 
epinephrine and norepinephrine. Therefore, injection of these agents into patients 
receiving thyroid preparations increases the risk of precipitating coronary insufficiency, 
especially in patients with coronary artery disease. Careful observation is required. 
Drug/Laboratory Test Interactions – The following drugs or moieties are known to 
interfere with laboratory tests performed in patients on thyroid hormone therapy: 
androgens, corticosteroids, estrogens, oral contraceptives containing estrogens, iodine-
containing preparations and the numerous preparations containing salicylates. 
1. Changes in TBg concentration should be taken into consideration in the 
interpretation of T4 and T3 values. In such cases, the unbound (free) hormone 
should be measured. Pregnancy, estrogens and estrogen-containing oral 
contraceptives increase TBg concentrations. TBg may also be increased during 
infectious hepatitis. Decreases in TBg concentrations are observed in nephrosis, 
acromegaly and after androgen or corticosteroid therapy. Familial hyper- or hypo-
thyroxinebinding-globulinemias have been described. The incidence of TBg 
deficiency approximates 1 in 9000. The binding of thyroxine by thyroxine-binding 
prealbumin (TBPA) is inhibited by salicylates. 
2. Medicinal or dietary iodine interferes with all in vivo tests of radioiodine uptake, 
producing low uptakes which may not be reflective of a true decrease in hormone 
synthesis. 
3. The persistence of clinical and laboratory evidence of hypothyroidism in spite of 
adequate dosage replacement indicates either poor patient compliance, poor 


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absorption, excessive fecal loss, or inactivity of the preparation. Intracellular 
resistance to thyroid hormone is quite rare. 
Carcinogenesis, Mutagenesis and Impairment of Fertility – A reportedly apparent 
association between prolonged thyroid therapy and breast cancer has not been confirmed 
and patients on thyroid for established indications should not discontinue therapy. No 
confirmatory long-term studies in animals have been performed to evaluate carcinogenic 
potential, mutagenicity, or impairment of fertility in either males or females. 
Pregnancy – Category A. Thyroid hormones do not readily cross the placental barrier. The 
clinical experience to date does not indicate any adverse effect on fetuses when thyroid 
hormones are administered to pregnant women. On the basis of current knowledge, 
thyroid replacement therapy to hypothyroid women should not be discontinued during 
pregnancy. 
Nursing Mothers – Minimal amounts of thyroid hormones are excreted in human milk. 
Thyroid is not associated with serious adverse reactions and does not have a known 
tumorigenic potential. 
However, caution should be exercised when thyroid is administered to a nursing woman. 
Geriatric Use – Clinical studies of liothyronine sodium did not include sufficient numbers of 
subjects aged 65 and over to determine whether they respond differently from younger 
subjects. Other reported clinical experience has not identified differences in responses 
between the elderly and younger patients. In general, dose selection for an elderly patient 
should be cautious, usually starting at the low end of the dosing range, reflecting the 


202 
 
greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant 
disease or other drug therapy. This drug is known to be substantially excreted by the 
kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired 
renal function. Because elderly patients are more likely to have decreased renal function, 
care should be taken in dose selection, and it may be useful to monitor renal function. 
Pediatric Use – Pregnant mothers provide little or no thyroid hormone to the fetus. The 
incidence of congenital hypothyroidism is relatively high (1:4000) and the hypothyroid fetus 
would not derive any benefit from the small amounts of hormone crossing the placental 
barrier. Routine determinations of serum T4 and/or TSH is strongly advised in neonates in 
view of the deleterious effects of thyroid deficiency on growth and development. 
Treatment should be initiated immediately upon diagnosis and maintained for life, unless 
transient hypothyroidism is suspected, in which case, therapy may be interrupted for 2 to 8 
weeks after the age of 3 years to reassess the condition. Cessation of therapy is justified in 
patients who have maintained a normal TSH during those 2 to 8 weeks. 
ADVERSE REACTIONS 
Adverse reactions, other than those indicative of hyperthyroidism because of therapeutic 
overdosage, either initially or during the maintenance period are rare (see OVERDOSAGE). 
In rare instances, allergic skin reactions have been reported with Cytomel 
(liothyronine sodium) Tablets. 


203 
 
OVERDOSAGE 
Signs and Symptoms – Headache, irritability, nervousness, sweating, arrhythmia (including 
tachycardia), increased bowel motility and menstrual irregularities. Angina pectoris or 
congestive heart failure may be induced or aggravated. Shock may also develop. Massive 
overdosage may result in symptoms resembling thyroid storm. Chronic excessive dosage 
will produce the signs and symptoms of hyperthyroidism. 
Treatment Of Overdosage – Dosage should be reduced or therapy temporarily 
discontinued if signs and symptoms of overdosage appear. Treatment may be reinstituted 
at a lower dosage. In normal individuals, normal hypothalamic-pituitary-thyroid axis 
function is restored in 6 to 8 weeks after thyroid suppression. 
Treatment of acute massive thyroid hormone overdosage is aimed at reducing 
gastrointestinal absorption of the drugs and counteracting central and peripheral effects, 
mainly those of increased sympathetic activity. Vomiting may be induced initially if further 
gastrointestinal absorption can reasonably be prevented and barring contraindications such 
as coma, convulsions, or loss of the gagging reflex. Treatment is symptomatic and 
supportive. Oxygen may be administered and ventilation maintained. Cardiac glycosides 
may be indicated if congestive heart failure develops. Measures to control fever, 
hypoglycemia, or fluid loss should be instituted if needed. Antiadrenergic agents, 
particularly propranolol, have been used advantageously in the treatment of increased 
sympathetic activity. Propranolol may be administered intravenously at a dosage of 1 to 3 


204 
 
mg over a 10-minute period or orally, 80 to 160 mg/day, especially when no 
contraindications exist for its use. 
DOSAGE AND ADMINISTRATION 
The dosage of thyroid hormones is determined by the indication and must in every case be 
individualized according to patient response and laboratory findings. 
Cytomel (liothyronine sodium) Tablets are intended for oral administration; once-a-day dosage 
is recommended. Although liothyronine sodium has a rapid cutoff, its metabolic effects persist 
for a few days following discontinuance. 
Mild Hypothyroidism: Recommended starting dosage is 25 mcg daily. Daily dosage then may 
be increased by up to 25 mcg every 1 or 2 weeks. Usual maintenance dose is 25 to75mcg 
daily. 
The rapid onset and dissipation of action of liothyronine sodium (T3), as compared with 
levothyroxine sodium (T4), has led some clinicians to prefer its use in patients who might be 
more susceptible to the untoward effects of thyroid medication. However, the wide swings in 
serum T3 levels that follow its administration and the possibility of more pronounced 
cardiovascular side effects tend to counterbalance the stated advantages. 
Cytomel (liothyronine sodium) Tablets may be used in preference to levothyroxine (T4) during 
radioisotope scanning procedures, since induction of hypothyroidism in those cases is more 
abrupt and can be of shorter duration. It may also be preferred when impairment of peripheral 
conversion of T4 to T3 is suspected. 
Myxedema: Recommended starting dosage is 5 mcg daily. This may be increased by 5 to 10 
mcg daily every 1 or 2 weeks. When 25 mcg daily is reached, dosage may be increased by 5 to 
25 mcg every 1 or 2 weeks until a satisfactory therapeutic response is attained. Usual 
maintenance dose is 50 to 100 mcg daily. 


205 
 
Myxedema Coma: Myxedema coma is usually precipitated in the hypothyroid patient of long 
standing by intercurrent illness or drugs such as sedatives and anesthetics and should be 
considered a medical emergency. 
An intravenous preparation of liothyronine sodium is marketed by Jones Pharma 
Incorporated, under the trade name Triostat® for use in myxedema coma/precoma. 
Congenital Hypothyroidism:  Recommended starting dosage is 5 mcg daily, with a 5 mcg 
increment every 3 to 4 days until the desired response is achieved. Infants a few months old 
may require only 20 mcg daily for maintenance. At 1 year, 50 mcg daily may be required. 
Above 3 years, full adult dosage may be necessary (see PRECAUTIONS, Pediatric Use). 
Simple (non-toxic) Goiter: Recommended starting dosage is 5 mcg daily. This dosage may be 
increased by 5 to 10 mcg daily every 1 or 2 weeks. When 25 mcg daily is reached, dosage may 
be increased every week or two by 12.5 or 25 mcg. Usual maintenance dosage is 75 mcg daily. 
In the elderly or in pediatric patients, therapy should be started with 5 mcg daily and 
increased only by 5 mcg increments at the recommended intervals. 
When switching a patient to Cytomel (liothyronine sodium) Tablets from thyroid, 
Lthyroxine or thyroglobulin, discontinue the other medication, initiate Cytomel at a low 
dosage, and increase gradually according to the patient's response. When selecting a 
starting dosage, bear in mind that this drug has a rapid onset of action, and that residual 
effects of the other thyroid preparation may persist for the first several weeks of therapy. 
Thyroid Suppression Therapy: Administration of thyroid hormone in doses higher than 
those produced physiologically by the gland results in suppression of the production of 
endogenous hormone. This is the basis for the thyroid suppression test and is used as an 
aid in the diagnosis of patients with signs of mild hyperthyroidism in whom baseline 


206 
 
laboratory tests appear normal or to demonstrate thyroid gland autonomy in patients with 
Graves’ ophthalmopathy. 131I uptake is determined before and after the administration of 
the exogenous hormone. A 50% or greater suppression of uptake indicates a normal 
thyroid-pituitary axis and thus rules out thyroid gland autonomy. 
Cytomel (liothyronine sodium) Tablets are given in doses of 75 to 100 mcg/day for 7 days, 
and radioactive iodine uptake is determined before and after administration of the 
hormone. If thyroid function is under normal control, the radioiodine uptake will drop 
significantly after treatment. Cytomel (liothyronine sodium) Tablets should be administered 
cautiously to patients in whom there is a strong suspicion of thyroid gland autonomy, in 
view of the fact that the exogenous hormone effects will be additive to the endogenous 
source. 
HOW SUPPLIED 
Cytomel (liothyronine sodium) Tablets: 5 mcg in bottles of 100; 
25 mcg in bottles of 100; and 50 mcg in bottles of 100. 
5 mcg 100’s: NDC 52604-3414-1 
25 mcg 100’s: NDC 52604-3416-1 
50 mcg 100’s: NDC 52604-3417-1 
Store between 15° and 30°C (59° and 86°F). 
DATE OF ISSUANCE November 2001 
 


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Manufactured by: 
Schering Canada, Inc., 3535 Trans-Canada Highway, Pointe Claire, Quebec H9R 1B4 Canada 
Distributed by: 
Monarch Pharmaceuticals, Inc., Bristol, TN 37620 
    83-481648  Rev. 11/01 
 
--------------------------------------------------------------------------------------------------------------------- 
This is a representation of an electronic record that was signed electronically and 
this page is the manifestation of the electronic signature. 
--------------------------------------------------------------------------------------------------------------------- 
 /s/ 
--------------------- 
David Orloff 
5/17/02 12:30:24 PM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


208 
 
 
 
 
APPENDIX F 
IOTHYRONINE SODIUM- LIOTHYRONINE SODIUM TABLET MAYNE PHARMA 
---------- 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use LIOTHYRONINE 
SODIUM TABLETS safely and effectively. See full prescribing information for 
LIOTHYRONINE SODIUM TABLETS.  
LIOTHYRONINE SODIUM tablets, for oral use  
Initial U.S. Approval: 1956 
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS 
See full prescribing information for complete boxed warning. 
Thyroid hormones, including liothyronine sodium tablets, should not be used for the 
treatment of obesity or for weight loss. 
Doses beyond the range of daily hormonal requirements may produce serious or even 
life-threatening manifestations of toxicity (6, 7.7, 10). 
 
 
 
Indications and Usage (1.1, 1.2, 1.3) 
RECENT MAJOR 
CHANGES 
12/2018 
 
Dosage and Administration (2.1, 2.2, 2.3, 2.4, 2.5, 2.6) 
12/2018 
Contraindications (4) 
12/2018 
Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6) 
12/2018 
 
 
 
INDICATIONS AND 
USAGE 
 
Liothyronine sodium tablets are an L-triiodothyronine (T3) indicated for: 


209 
 
Hypothyroidism: As replacement in primary (thyroidal), secondary (pituitary), and 
tertiary (hypothalamic) congenital or acquired hypothyroidism (1.1) 
Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression: As an adjunct 
to surgery and radioiodine therapy in the management of well-differentiated thyroid 
cancer (1.2) 
Thyroid Suppression Test: As a diagnostic agent in suppression tests to differentiate 
suspected mild hyperthyroidism or thyroid gland autonomy (1.3) 
Limitations of Use: 
- Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in 
iodine-sufficient patients. (1) 
- Not indicated for treatment of hypothyroidism during the recovery phase of subacute 
thyroiditis. (1) 
DOSAGE AND ADMINISTRATION 
• Administer liothyronine sodium tablets orally once daily and individual dosage 
according to patient response and laboratory findings (2.1) 
• See full prescribing information for recommended dosage for hypothyroidism 
(2.2) TSH suppression in well differentiated thyroid cancer (2.3) and for thyroid 
suppression test (2.4) 
• When switching a patient to liothyronine sodium tablets, discontinue 
levothyroxine therapy and initiate liothyronine sodium 
• Adequacy of therapy determined with periodic monitoring of TSH and T3 levels 
as well as clinical status (2.6) 
DOSAGE FORMS AND STRENGTHS 
Tablets: 5 mcg, 25 mcg, 50 mcg (3) 
CONTRAINDICATIONS 
Uncorrected adrenal cortical insufficiency (4) 
WARNINGS AND PRECAUTIONS 
Cardiac adverse reactions in the elderly and in patients with underlying 
cardiovascular disease: Initiate liothyronine sodium tablets at less than the full 
replacement dose because of the increased risk of cardiac adverse reactions, 
including atrial fibrillation (2.3, 5.1, 8.5) 
Myxedema coma: Do not use oral thyroid hormone drug products to treat myxedema 
coma. (5.2) 
Acute adrenal crisis in patients with concomitant adrenal insufficiency: Treat with 
replacement glucocorticoids prior to initiation of liothyronine sodium tablets 
treatment (5.3) 
Prevention of hyperthyroidism or incomplete treatment of hypothyroidism: Proper 
dose titration and careful monitoring is critical to prevent the persistence of 
hypothyroidism or the development of hyperthyroidism. (5.4) 
 Worsening of diabetic control: Therapy in patients with diabetes mellitus may worsen 
glycemic    control and result in increased antidiabetic agent or insulin requirements. 


210 
 
Carefully monitor glycemic control after starting, changing, or discontinuing thyroid 
hormone therapy (5.5) 
   Decreased bone mineral density associated with thyroid hormone over-replacement: 
Over-replacement can increase bone resorption and decrease bone mineral density. 
Give the lowest effective dose (5.6) 
 
Most common adverse reactions for liothyronine sodium tablets are primarily those of 
hyperthyroidism due to therapeutic overdosage: arrhythmias, myocardial infarction, 
dyspnea, headache, nervousness, irritability, insomnia, tremors, muscle weakness, 
increased appetite, weight loss, diarrhea, heat intolerance, menstrual irregularities, and 
skin rash (6) 
To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 or 
FDA at 1-800FDA-1088 or www.fda.gov/medwatch. 
 
See full prescribing information for drugs that affect thyroid hormone pharmacokinetics 
and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and 
target tissue response) and may alter the therapeutic response to liothyronine sodium 
tablets (7) 
 
Pregnancy may require the use of higher doses of thyroid hormone (2.2, 8.1) 
See 17 for PATIENT COUNSELING INFORMATION. 
Revised: 3/2019 
 
FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: NOT FOR TREATMENT OF 
OBESITY OR FOR WEIGHT LOSS 1 INDICATIONS AND USAGE 
1.1 Hypothyroidism 
1.2 Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression 
1.3 Thyroid Suppression Test 
2 DOSAGE AND ADMINISTRATION 
2.1 General Principles of Dosing 
2.2 Recommended Dosage for Hypothyroidism 
2.3 Recommended Dosage for TSH Suppression in Well-Differentiated Thyroid Cancer 
2.4 Recommended Dosage for Thyroid Suppression Test 
2.5 Switching from Levothyroxine to Liothyronine Sodium Tablets 
2.6 Monitoring TSH and Triiodothyronine (T3) Levels 
 
 
 


211 
 
3 
DOSAGE FORMS AND STRENGTHS  
4  
CONTRAINDICATIONS  
5  WARNINGS AND PRECAUTIONS 
5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying 
Cardiovascular Disease 
5.2 Myxedema Coma 
5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency 
5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism 
5.5 Worsening of Diabetic Control 
5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-
Replacement 
6 ADVERSE REACTIONS  
7 DRUG INTERACTIONS 
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics 
7.2 Antidiabetic Therapy 
7.3 Oral Anticoagulants 
7.4 Digitalis Glycosides 
7.5 Antidepressant Therapy 
7.5 Antidepressant Therapy 
7.6 Ketamine 
7.7 Sympathomimetics 
 
7.8 Tyrosine-Kinase Inhibitors 
7.8 Tyrosine-Kinase Inhibitors 
7.9 Drug-Laboratory Test    
Interactions 
8  USE IN SPECIFIC 
POPULATIONS 
8.1 Pregnancy 
8.2 Lactation 
8.4 Pediatric Use 
8.5 Geriatric Use  
10 OVERDOSAGE 
11 DESCRIPTION 12 CLINICAL 
PHARMACOLOGY 
12.1 Mechanism of Action 


212 
 
12.2 Pharmacodynamics 
12.3 Pharmacokinetics 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, 
Impairment of Fertility  
16 HOW SUPPLIED/STORAGE AND HANDLING 
17 PATIENT COUNSELING INFORMATION 
 
* Sections or subsections omitted from the full prescribing information are not listed. 
 
FULL PRESCRIBING INFORMATION 
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS 
Thyroid hormones, including liothyronine sodium tablets, either alone or with other 
therapeutic agents, should not be used for the treatment of obesity or for weight 
loss. In euthyroid patients, doses within the range of daily hormonal requirements 
are ineffective for weight reduction. 
Larger doses may produce serious or even life-threatening manifestations of toxicity, 
particularly when given in association with sympathomimetic amines such as those used for 
their anorectic effects [see Adverse Reactions (6), Drug Interactions (7.7), and Overdosage 
(10)]. 
1 INDICATIONS AND USAGE 
1.1 Hypothyroidism 
Liothyronine sodium tablets are indicated as a replacement therapy in primary 
(thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired 
hypothyroidism. 
1.2 Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression 
Liothyronine sodium tablets are indicated as an adjunct to surgery and radioiodine 
therapy in the management of well-differentiated thyroid cancer. 
1.3 Thyroid Suppression Test 
Liothyronine sodium tablets are indicated as a diagnostic agent in suppression tests to 
differentiate suspected mild hyperthyroidism or thyroid gland autonomy. 


213 
 
Limitations of Use 
Limitations of Use 
 Liothyronine sodium tablets are not indicated for suppression of benign thyroid 
nodules and nontoxic diffuse goiter in iodine-sufficient patients as there are no 
clinical benefits and overtreatment with liothyronine sodium tablets may induce 
hyperthyroidism [see Warnings and Precautions (5.4)]. 
 Liothyronine sodium tablets are not indicated for treatment of hypothyroidism during 
the recovery phase of subacute thyroiditis. 
2 DOSAGE AND ADMINISTRATION 
6.3 2.1 General Principles of Dosing 
The dose of liothyronine sodium tablets for hypothyroidism or pituitary Thyroid-
Stimulating Hormone 
(TSH) suppression depends on a variety of factors including: the patient's age, body 
weight, cardiovascular status, concomitant medical conditions (including pregnancy), 
concomitant medications, co-administered food and the specific nature of the condition 
being treated [see Dosage and 
Administration (2.2, 2.3, 2.4), Warnings and Precautions (5), and Drug Interactions (7)]. 
Dosing must be individualized to account for these factors and dose adjustments made 
based on periodic assessment of the patient's clinical response and laboratory parameters 
[see Dosage and Administration (2.4)]. 
Administer liothyronine sodium tablets orally once daily. 
2.2 Recommended Dosage for 
Hypothyroidism Adults 
The recommended starting dosage is 25 mcg orally once daily. Increase the dose by 25 mcg 
daily every 1 or 2 weeks, if needed. The usual maintenance dose is 25 mcg to 75 mcg once 
daily. 
For elderly patients or patients with underlying cardiac disease, start with liothyronine 
sodium tablets 5 mcg once daily and increase by 5 mcg increments at the recommended 
intervals. 
Serum TSH is not a reliable measure of liothyronine sodium tablets dose adequacy in 
patients with secondary or tertiary hypothyroidism and should not be used to monitor 
therapy. Use the serum T3 level to monitor adequacy of therapy in this patient population. 
Pediatric Patients 
The recommended starting dosage is 5 mcg once daily, with a 5 mcg increase every 3 to 4 
days until the desired response is achieved. Infants a few months old may require 20 mcg 


214 
 
once daily for maintenance. At 1 year of age, 50 mcg once daily may be required. Above 3 
years of age, the full adult dosage may be necessary [see Use in Specific Populations (8.4)]. 
Newborns (0 to 3 months) at Risk for Cardiac Failure: 
Consider a lower starting dose in infants at risk for cardiac failure. Increase the dose as 
needed based on clinical and laboratory response. 
Pediatric Patients at Risk for Hyperactivity 
To minimize the risk of hyperactivity in pediatric patients, start at one-fourth the 
recommended full replacement dose, and increase on a weekly basis by one-fourth the full 
recommended replacement dose until the full recommended replacement dose is reached. 
Pregnancy 
Pre-existing Hypothyroidism: Thyroid hormone dose requirements may increase during 
pregnancy. Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at 
minimum, during each trimester of pregnancy. In patients with primary hypothyroidism, 
maintain serum TSH in the trimesterspecific reference range. For patients with serum 
TSH above the normal trimester-specific range, increase the dose of thyroid hormone 
and measure TSH every 4 weeks until a stable dose is reached and serum TSH is within 
the normal trimester-specific range. Reduce thyroid hormone dosage to prepregnancy 
levels immediately after delivery and measure serum TSH levels 4 to 8 weeks 
postpartum to ensure thyroid hormone dose is appropriate. 
2.3 Recommended Dosage for TSH Suppression in Well-Differentiated Thyroid Cancer 
The dose of liothyronine sodium tablets should target TSH levels within the desired 
therapeutic range. 
This may require higher doses, depending on the target level for TSH suppression. 
2.4 Recommended Dosage for Thyroid Suppression Test 
The recommended dose is 75 mcg to 100 mcg daily for 7 days, with radioactive iodine 
uptake being determined before and after the 7 day administration of liothyronine 
sodium tablets. If thyroid function is normal, the radioiodine uptake will drop 
significantly after treatment. A 50% or greater suppression of uptake indicates a normal 
thyroid-pituitary axis. 
2.5 Switching from Levothyroxine to Liothyronine Sodium Tablets 
Liothyronine sodium tablets has a rapid onset of action and residual effects of the 
other thyroid preparation may persist for the first several weeks after initiating 
liothyronine sodium tablets therapy. When switching a patient to liothyronine sodium 
tablets, discontinue levothyroxine therapy and initiate liothyronine sodium tablets at a 
low dosage. Gradually increase the liothyronine sodium tablets dose according to the 
patient's response. 


215 
 
2.6 Monitoring TSH and Triiodothyronine (T3) Levels 
Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical 
evaluation. Persistent clinical and laboratory evidence of hypothyroidism despite an 
apparent adequate replacement dose of liothyronine sodium tablets may be evidence of 
inadequate absorption, poor compliance, drug interactions, or a combination of these 
factors. 
Adults 
In adult patients with primary hypothyroidism, monitor serum TSH periodically after 
initiation of the therapy or any change in dose. To check the immediate response to 
therapy before the TSH has had a chance to respond or if your patient's status needs to 
be assessed prior to that point, measurement of total T3 would be most appropriate. In 
patients on a stable and appropriate replacement dose, evaluate clinical and biochemical 
response every 6 to 12 months and whenever there is a change in the patient's clinical 
status. 
Pediatrics 
In pediatric patients with hypothyroidism, assess the adequacy of replacement therapy by 
measuring serum TSH and T3 levels. For pediatric patients three years of age and older, the 
recommended monitoring is every 3 to 12 months thereafter, following dose stabilization 
until growth and puberty are completed. Poor compliance or abnormal values may 
necessitate more frequent monitoring. Perform routine clinical examination, including 
assessment of development, mental and physical growth, and bone maturation, at regular 
intervals. 
While the general aim of therapy is to normalize the serum TSH level, TSH may not 
normalize in some patients due to in utero hypothyroidism causing a resetting of pituitary-
thyroid feedback. Failure of the serum TSH to decrease below 20 IU per liter after initiation 
of liothyronine sodium tablets therapy may indicate the child is not receiving adequate 
therapy. Assess compliance, dose of medication administered, and method of 
administration prior to increasing the dose of liothyronine sodium tablets[see Warnings 
and Precautions (5.1) and Use in Specific Populations (8.4)]. 
Secondary and Tertiary Hypothyroidism 
Monitor serum T3 levels and maintain in the normal range. 
3 DOSAGE FORMS AND STRENGTHS 
Tablets (round, flat, white to off-white) available as follows: 
5 mcg: debossed "5" over "220" on one side and plain on the other 
25 mcg: debossed "25" above the score and "222" below the score on one side and 
plain on the other 


216 
 
50 mcg: debossed "50" above the score and "223" below the score on one side and plain 
on the other 
4 CONTRAINDICATIONS 
Liothyronine sodium tablets are contraindicated in patients with uncorrected adrenal 
insufficiency [see Warnings and Precautions (5.3)]. 
5 WARNINGS AND PRECAUTIONS 
5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying 
Cardiovascular Disease 
Overtreatment with thyroid hormone may cause an increase in heart rate, cardiac wall 
thickness, and cardiac contractility and may precipitate angina or arrhythmias, 
particularly in patients with cardiovascular disease and in elderly patients. Initiate 
liothyronine sodium tablets therapy in this population at lower doses than those 
recommended in younger individuals or in patients without cardiac disease [see Dosage 
and Administration (2.3) and Use in Specific Populations (8.5)]. 
Monitor for cardiac arrhythmias during surgical procedures in patients with coronary 
artery disease receiving suppressive liothyronine sodium tablets therapy. Monitor 
patients receiving concomitant liothyronine sodium tablets and sympathomimetic 
agents for signs and symptoms of coronary insufficiency. If cardiovascular symptoms 
develop or worsen, reduce or withhold the liothyronine sodium tablets dose for one 
week and restart at a lower dose. 
5.2 Myxedema Coma 
Myxedema coma is a life-threatening emergency characterized by poor circulation and 
hypometabolism, and may result in unpredictable absorption of thyroid hormone from 
the gastrointestinal tract. Use of oral thyroid hormone drug products is not 
recommended to treat myxedema coma. Administer thyroid hormone products 
formulated for intravenous administration to treat myxedema coma. 
5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency 
Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid 
hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute 
adrenal crisis in patients with adrenal insufficiency. Treat patients with adrenal 
insufficiency with replacement glucocorticoids prior to initiating treatment with 
liothyronine sodium tablets[see Contraindications (4)]. 


217 
 
5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism 
Liothyronine sodium tablets has a narrow therapeutic index. Over- or undertreatment 
with liothyronine sodium tablets may have negative effects on growth and 
development, cardiovascular function, bone metabolism, reproductive function, 
cognitive function, emotional state, gastrointestinal function, and on glucose and lipid 
metabolism. Titrate the dose of liothyronine sodium tablets carefully and monitor 
response to titration to avoid these effects [see Dosage and Administration (2.4)]. 
Monitor for the presence of drug or food interactions when using liothyronine sodium 
tablets and adjust the dose as necessary [see Drug Interactions (7) and Clinical 
Pharmacology (12.3)]. 
5.5 Worsening of Diabetic Control 
Addition of thyroid hormone therapy in patients with diabetes mellitus may worsen 
glycemic control and result in increased antidiabetic agent or insulin requirements. 
Carefully monitor glycemic control after starting, changing, or discontinuing liothyronine 
sodium tablets[see Drug Interactions (7.2)]. 
5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-
Replacement 
Increased bone resorption and decreased bone mineral density may occur as a result of 
thyroid hormone over-replacement, particularly in post-menopausal women. 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. Administer the minimum dose of 
liothyronine sodium tablets that achieves the desired clinical and biochemical response 
to mitigate against this risk. 
6 ADVERSE REACTIONS 
Adverse reactions associated with liothyronine sodium tablets therapy are primarily 
those of hyperthyroidism due to therapeutic overdosage [see Warnings and 
Precautions (5.4) and Overdosage (10)]. 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 and cramps 


218 
 
Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, 
heart failure, angina, myocardial infarction, cardiac arrest 
Respiratory: dyspnea 
Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests 
Dermatologic: hair loss, flushing 
Endocrine: decreased bone mineral density 
Reproductive: menstrual irregularities, impaired fertility 
Adverse Reactions in Pediatric Patients 
Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in 
pediatric patients receiving thyroid replacement therapy. Overtreatment may result in 
craniosynostosis in infants and premature closure of the epiphyses in pediatric 
patients with resultant compromised adult height. 
Hypersensitivity Reactions 
Hypersensitivity reactions to inactive ingredients have occurred in patients treated 
with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, 
angioedema, various gastrointestinal symptoms (abdominal pain, nausea, vomiting 
and diarrhea), fever, arthralgia, serum sickness and wheezing. 
7 DRUG INTERACTIONS 
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics 
Many drugs can exert effects on thyroid hormone pharmacokinetics (e.g. absorption, 
synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter 
the therapeutic response to liothyronine sodium tablets (see Tables 1 – 4). 
Table 1: Drugs That May Decrease T3 Absorption (Hypothyroidism) 
Potential impact: Concurrent use may reduce the efficacy of liothyronine sodium 
tablets by binding and delaying or preventing absorption, potentially resulting in 
hypothyroidism. 
DRUG OR DRUG CLASS 
EFFECT 
Bile Acid Sequestrants 
-Colesevelam 
                  Bile acid sequestrants and ion exchange resins are known to decrease 
-Cholestyramine thyroid hormones absorption. Administer liothyronine sodium 
tablets 
-Colestipol at least 4 hours prior to these drugs or monitor 
thyrotropin- 


219 
 
Ion Exchange Resins stimulating hormone 
TSH) levels. 
-Kayexalate 
-Sevelamer 
Table 2: Drugs That May Alter Triiodothyronine (T3) Serum Transport Without 
Affecting Free Thyroxine (FT4) Concentration (Euthyroidism) 
DRUG OR DRUG CLASS 
EFFECT 
Clofibrate 
Estrogen-
containing 
oral 
Contracepti
on  
Estrogens (oral) These drugs may increase serum thyroxine-binding globulin (TBG) 
Heroin / Methadone concentration. 
5-
Fluorouraci
l Mitotane 
Tamoxifen 
Androgens / Anabolic 
Steroids  
Asparaginase 
These drugs may decrease serum TBG concentration. 
Glucocorticoids 
Slow-Release 
Nicotinic Acid 
Salicylates inhibit binding of T4 and T3 to TBG and 
transthyretin. An initial increase in serum FT4 is followed by return of FT4 to 
normal Salicylates (>2 g/day) 
levels with sustained therapeutic serum salicylate concentrations, 
although total T4 levels may decrease by as much as 30%. 
Other drugs:These drugs may cause protein binding site displacement. 
Carbamazepine Furosemide has been shown to inhibit the protein binding of T4 to 
Furosemide (>80 mg TBG and albumin, causing an increased free-T4 fraction in serum. 
IV) Furosemide competes for T4-binding sites on TBG, prealbumin, and 
Heparin albumin, so that a single high dose can acutely lower the total T4 
Hydantoins level. Phenytoin and carbamazepine reduce serum protein binding of Non-
Steroidal Anti- thyroid hormones, and total and FT4 may be reduced by 20% to 40%, 
inflammatory Drugs but most patients have normal serum TSH levels and are clinically - 
Fenamates euthyroid. Closely monitor thyroid hormone parameters. 


220 
 
Table 3: Drugs That May Alter Hepatic Metabolism of Thyroid hormones 
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme 
activity may cause increased hepatic degradation of thyroid hormones, resulting 
in increased liothyronine sodium tablets requirements. 
DRUG OR DRUG CLASS 
EFFECT 
Phenobarbital has been shown to reduce the response to thyroxine. 
Phenobarbital increases L-thyroxine metabolism by inducing uridine 5'-
diphospho-glucuronosyltransferase (UGT) and leads to a lower 
Phenobarbital  
T4 serum levels. Changes in thyroid status may occur if barbiturates 
Rifampin are added or withdrawn from patients being treated for 
hypothyroidism. Rifampin has been shown to 
accelerate the metabolism of thyroid 
hormones. 
TABLE 4: DRUGS THAT MAY DECREASE CONVERSION OF T4 TO T3 
Potential impact: 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. 
DRUG OR DRUG CLASS 
EFFECT 
In patients treated with large doses of propranolol (>160 mg/day), T3 
Beta-adrenergic and T4 levels change, TSH levels remain normal, and  
patients are antagonists (e.g., clinically euthyroid. 
 Actions of particular beta-adrenergic Propranolol >160 antagonists  
may be impaired when a hypothyroid patient is converted mg/day)  
to the euthyroid state.  
Short-term administration of large doses of glucocorticoids may 
Glucocorticoids (e.g., decrease serum T3 concentrations by 30% with minimal 
change in Dexamethasone ≥4 serum T4 levels. However, long-term 
glucocorticoid therapy may mg/day) result in slightly decreased T3 and T4 
levels due to decreased TBG production (see above). 
Amiodarone inhibits peripheral conversion of 
levothyroxine (T4) to Other drugs: triiodothyronine (T3) and may cause isolated 
biochemical changes Amiodarone (increase in serum free-T4, and decreased or 
normal free-T3) in clinically euthyroid patients. 


221 
 
7.2 Antidiabetic Therapy 
Addition of liothyronine sodium tablets therapy in patients with diabetes mellitus may 
worsen glycemic control and result in increased antidiabetic agent or insulin requirements. 
Carefully monitor glycemic control, especially when liothyronine sodium tablets are started, 
changed, or discontinued [see Warnings and Precautions (5.5)]. 
7.3 Oral Anticoagulants 
Liothyronine sodium tablets 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 liothyronine sodium tablets dose is increased. Closely 
monitor coagulation tests to permit appropriate and timely dosage adjustments. 
7.4 Digitalis Glycosides 
Liothyronine sodium tablets may reduce the therapeutic effects of digitalis glycosides. 
Serum digitalis glycoside levels may be decreased when a hypothyroid patient becomes 
euthyroid, necessitating an increase in the dose of digitalis glycosides. 
7.5 Antidepressant Therapy 
Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) 
antidepressants and liothyronine sodium tablets 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 central nervous system 
stimulation. Liothyronine sodium tablets may accelerate the onset of action of tricyclics. 
Administration of sertraline in patients stabilized on liothyronine sodium tablets may result 
in increased liothyronine sodium tablets requirements. 
7.6 Ketamine 
Concurrent use of ketamine and liothyronine sodium tablets may produce marked 
hypertension and tachycardia. Closely monitor blood pressure and heart rate in these 
patients. 
7.7 Sympathomimetics 
Concurrent use of sympathomimetics and liothyronine sodium tablets 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. 


222 
 
7.8 Tyrosine-Kinase Inhibitors 
Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. 
Closely monitor TSH levels in such patients. 
7.9 Drug-Laboratory Test Interactions 
Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and 
evaluate unbound (free) hormone in this circumstance. Pregnancy, infectious hepatitis, 
estrogens, estrogencontaining oral contraceptives, and acute intermittent porphyria 
increase TBG concentrations. Nephrosis, severe hypoproteinemia, severe liver disease, 
acromegaly, androgens and corticosteroids decrease TBG concentration. Familial hyper- 
or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG 
deficiency approximating 1 in 9000. 
8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
Risk Summary 
Experience with liothyronine use in pregnant women, including data from post-marketing 
studies, have not reported increased rates of major birth defects or miscarriages (see 
Data). There are risks to the mother and fetus associated with untreated hypothyroidism 
in pregnancy. Since TSH levels may increase during pregnancy, TSH should be monitored 
and liothyronine sodium tablets dosage adjusted during pregnancy (see Clinical 
Considerations). There are no animal studies conducted with liothyronine during 
pregnancy. Liothyronine sodium tablets should not be discontinued during pregnancy and 
hypothyroidism diagnosed during pregnancy should be promptly treated. 
The estimated background risk of major birth defects and miscarriage for the indicated 
population is unknown. In the U.S. general population, the estimated background risk 
of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% 
and 15 to 20%, respectively. 
Clinical Considerations 
Disease-associated maternal and/or embryo/fetal risk 
Maternal hypothyroidism during pregnancy is associated with a higher rate of 
complications, including spontaneous abortion, gestational hypertension, pre-eclampsia, 
stillbirth, and premature delivery. Untreated maternal hypothyroidism may have an 
adverse effect on fetal neurocognitive development. 
Dose adjustments during pregnancy and the postpartum period 


223 
 
Pregnancy may increase liothyronine sodium tablets requirements. Serum TSH levels 
should be monitored and the liothyronine sodium tablets dosage adjusted during 
pregnancy. Since postpartum TSH levels are similar to preconception values, the 
liothyronine sodium tablets dosage should return to the pre-pregnancy dose immediately 
after delivery [see Dosage and Administration (2.3)]. 
Data 
Human Data 
Liothyronine is approved for use as a replacement therapy for hypothyroidism. Data 
from postmarketing studies have not reported increased rates of fetal 
malformations, miscarriages, or other adverse maternal or fetal outcomes 
associated with liothyronine use in pregnant women. 
8.2 Lactation 
Risk Summary 
Limited published studies report that liothyronine is present in human milk. However, 
there is insufficient information to determine the effects of liothyronine on the breastfed 
infant and no available information on the effects of liothyronine on milk production. The 
developmental and health benefits of breastfeeding should be considered along with the 
mother's clinical need for liothyronine sodium tablets and any potential adverse effects on 
the breastfed infant from liothyronine sodium tablets or from the underlying maternal 
condition. 
8.4 Pediatric Use 
The initial dose of liothyronine sodium tablets varies with age and body weight. Dosing 
adjustments are based on an assessment of the individual patient's clinical and laboratory 
parameters [see Dosage and Administration (2.3, 2.4)]. 
In pediatric patients in whom a diagnosis of permanent hypothyroidism has not been 
established, discontinue thyroid hormone for a trial period, but only after the child is at 
least 3 years of age. Obtain serum TSH, T4, and T3 levels at the end of the trial period, and 
use laboratory test results and clinical assessments to guide diagnosis and treatment, if 
warranted [see Dosage and Administration (2.6)]. 
Congenital Hypothyroidism [see Dosage and Administration (2.2, 2.6)] 
Rapid restoration of normal serum T4 concentrations is essential for preventing the 
adverse effects of congenital hypothyroidism on intellectual development as well as on 
overall physical growth and maturation. Therefore, initiate thyroid hormone immediately 
upon diagnosis. Thyroid hormone is generally continued for life in these patients. 
Closely monitor infants during the first 2 weeks of thyroid hormone therapy for cardiac 
overload, arrhythmias, and aspiration from avid suckling. 


224 
 
Closely monitor patients to avoid undertreatment or overtreatment. Undertreatment may 
have deleterious effects on intellectual development and linear growth. Overtreatment is 
associated with craniosynostosis in infants, may adversely affect the tempo of brain 
maturation, and may accelerate the bone age and result in premature epiphyseal closure 
and compromised adult stature [see Dosage and Administration (2.6) and Adverse Reactions 
(6)]. 
Acquired Hypothyroidism in Pediatric Patients 
Closely monitor patients to avoid undertreatment and overtreatment. Undertreatment 
may result in poor school performance due to impaired concentration and slowed 
mentation and in reduced adult height. Overtreatment may accelerate the bone age and 
result in premature epiphyseal closure and compromised adult stature. 
Treated children may manifest a period of catch-up growth, which may be adequate in 
some cases to normalize adult height. In children with severe or prolonged hypothyroidism, 
catch-up growth may not be adequate to normalize adult height [see Adverse Reactions 
(6)]. 
8.5 Geriatric Use 
Because of the increased prevalence of cardiovascular disease among the elderly, initiate 
liothyronine sodium tablets at less than the full replacement dose [see Dosage and 
Administration (2.3) and Warnings and Precautions (5.1)]. Atrial arrhythmias can occur in 
elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with 
thyroid hormone overtreatment in the elderly. 
common of the arrhythmias observed with thyroid hormone overtreatment in the elderly. 
10 OVERDOSAGE 
The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and 
Precautions (5.4) and Adverse Reactions (6)]. In addition, confusion and disorientation may 
occur. Cerebral embolism, seizure, shock, coma, and death have been reported. Symptoms 
may not necessarily be evident or may not appear until several days after ingestion. 
Reduce the liothyronine sodium tablets dose or temporarily discontinued if signs or 
symptoms of overdosage occur. Initiate appropriate supportive treatment as dictated by 
the patient's medical status. 
For current information on the management of poisoning or overdosage, contact the 
National Poison Control Center at 1-800-222-1222 or www.poison.org. 
11 DESCRIPTION 
Liothyronine sodium tablets contain the active ingredient, liothyronine (L-
triiodothyronine or LT3), a synthetic form of a thyroid hormone liothyronine in sodium 


225 
 
salt form. It is chemically designated as LTyrosine, O-(4-hydroxy-3-iodophenyl)-3,5-diiodo-
, monosodium salt. The molecular formula, molecular weight and structural formula of 
liothyronine sodium are given below. 
 
        C15H11I3NNaO4                 M.W.672.96 
Liothyronine sodium tablets contain liothyronine sodium equivalent to liothyronine in 5 
mcg, 25 mcg, and 50 mcg. Inactive ingredients consist of calcium sulfate, microcrystalline 
cellulose, hypromellose, talc, and colloidal silicon dioxide. 
12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
Thyroid hormones exert their physiologic actions through control of DNA transcription and 
protein synthesis. Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell nucleus 
and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor 
complex activates gene transcription and synthesis of messenger RNA and cytoplasmic 
proteins. 
The physiological actions of thyroid hormones are produced predominantly by T3, the 
majority of which (approximately 80%) is derived from T4 by deiodination in peripheral 
tissues. 
12.2 Pharmacodynamics 
The onset of activity of liothyronine sodium occurs within a few hours. Maximum 
pharmacologic response occurs within 2 or 3 days. 
12.3 Pharmacokinetics 
Absorption 
T3 is almost totally absorbed, 95 percent in 4 hours. The hormones contained in the 
natural preparations are absorbed in a manner similar to the synthetic hormones. 
Distribution 
Liothyronine sodium (T3) is not firmly bound to serum protein. The higher affinity of 
levothyroxine 


226 
 
(T4) for both thyroid-binding globulin and thyroid-binding prealbumin as compared to 
triiodothyronine (T3) partially explains the higher serum levels and longer half-life of the 
former hormone. Both protein-bound hormones exist in reverse equilibrium with minute 
amounts of free hormone, the latter accounting for the metabolic activity. 
Elimination 
Metabolism 
The major pathway of thyroid hormone metabolism is through sequential deiodination. 
Approximately 80% of circulating T3 is derived from peripheral T4 by monodeiodination. 
The liver is the major site of degradation for both T4 and T3. T3 is further deiodinated to 
diiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides 
and sulfates and excreted directly into the bile and gut where they undergo enterohepatic 
recirculation. 
Excretion 
Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated 
hormone reaches the colon unchanged and is eliminated in the feces. The biological half-
life is about 2-1/2 days. 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
Animal studies have not been performed to evaluate the carcinogenic potential, mutagenic 
potential or effects on fertility of liothyronine sodium. 
16 HOW SUPPLIED/STORAGE AND HANDLING 
Liothyronine sodium tablets, USP (round, flat, white to off-white) are supplied as follows: 
STRENGTH 
TABLET MARKINGS 
NDC – BOTTLES OF 100 
debossed "5" over "220" on 
5 mcg 
51862-320-01 
one side and plain 
on the other 
debossed "25" 
above the score 
and "222" below 
the 
25 mcg 
51862-321-01 
score on one side 
and plain on the 
other debossed 


227 
 
"50" above the 
score and "223" 
below the 
50 mcg 
51862-322-01 
score on one side 
and plain on the 
other 
Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] 
17 PATIENT COUNSELING INFORMATION 
Dosing and Administration 
Instruct patients that liothyronine sodium tablets should only be taken as directed by 
their healthcare provider. 
Instruct patients to notify their healthcare provider should they become pregnant or 
breastfeeding or are thinking of becoming pregnant, while taking liothyronine sodium 
tablets. 
Important Information 
Inform patients that the liothyronine in liothyronine sodium tablets are intended to 
replace a hormone that is normally produced by the thyroid gland. Generally 
replacement therapy is to be taken for life. Inform patients that liothyronine sodium 
tablets should not be used as a primary or adjunctive therapy in a weight control 
program. 
Instruct patients to notify their healthcare provider if they are taking any other 
medications, including prescription and over-the-counter preparations. 
Instruct patients to notify their healthcare provider of any other medical conditions, 
particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland 
problems, as the dose of medications used to control these other conditions may need to 
be adjusted while taking liothyronine sodium tablets. If patents are taking anticoagulants 
(blood thinners), their clotting status should be checked frequently. 
 Instruct patients to notify their physician or dentist if they are taking liothyronine 
sodium tablets prior to any surgery. 
Adverse Reactions 
 Instruct patients to notify their healthcare provider if they experience any of the 
following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, leg 
cramps, headache, nervousness, irritability, sleeplessness, tremors, change in 
appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat 
intolerance, fever, changes in menstrual periods, hives or skin rash, or any other 
unusual medical event [see Adverse Reactions (6)]. 


228 
 
 Inform patients that partial hair loss may occur rarely during the first few months of 
liothyronine sodium tablets therapy; this is usually temporary [see Adverse Reactions 
(6)]. 
Manufactured by: 
7 MAYNE PHARMA  
Greenville, NC 27834 
61859 
Rev 03/2019 
PRINCIPAL DISPLAY PANEL - 5 mcg Tablet Bottle Label 
NDC 51862-320-01 
8 LIOTHYRONINE SODIUM TABLETS, USP 
5 mcg 
Rx Only 
100 Tablets 
maynepharma 
 
PRINCIPAL DISPLAY PANEL - 25 mcg Tablet Bottle Label 
NDC 51862-321-01 
9 LIOTHYRONINE SODIUM TABLETS, USP 
25 mcg 
Rx Only 
100 Tablets 
maynepharma 


229 
 
 
PRINCIPAL DISPLAY PANEL - 50 mcg Tablet Bottle Label 
NDC 51862-322-01 
10 LIOTHYRONINE SODIUM TABLETS, USP 
50 mcg 
Rx Only 
100 Tablets 
maynepharma 
 
LIOTHYRONINE SODIUM   
liothyronine sodium tablet 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:51862-320 
Route of Administration 
ORAL 


230 
 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
Liothyronine Sodium (UNII: GCA9VV7D2N) (liothyronine - UNII:06LU7C9H1V) 
 
liothyronine 
5 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
calcium sulfate, unspecified form (UNII: WAT0DDB505) 
 
  
microcrystalline cellulose (UNII: OP1R32D61U) 
 
  
hypromellose, unspecified (UNII: 3NXW29V3WO) 
 
  
talc (UNII: 7SEV7J4R1U) 
 
  
silicon dioxide (UNII: ETJ7Z6XBU4) 
 
  
 
 
Product Characteristics 
 
Color 
WHITE 
Score 
 
no score 
Shape 
ROUND 
Size 
 
7mm 
Flavor 
 
Imprint Code 
 
5;220 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
 
Marketing Start 
Date 
Marketing End Date 
1 NDC:51862-320- 
01 
100 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
 
01/01/2018 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 


231 
 
ANDA 
ANDA090097 
01/01/2018 
 
 
 
 
 
Ingredient Name 
 
Basis of Strength 
Strength 
Liothyronine Sodium (UNII: GCA9VV7D2N) (liothyronine - UNII:06LU7C9H1V) 
 
liothyronine 
25 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
calcium sulfate, unspecified form (UNII: WAT0DDB505) 
 
  
microcrystalline cellulose (UNII: OP1R32D61U) 
 
  
hypromellose, unspecified (UNII: 3NXW29V3WO) 
 
  
talc (UNII: 7SEV7J4R1U) 
 
  
silicon dioxide (UNII: ETJ7Z6XBU4) 
 
  
 
 
Product Characteristics 
 
Color 
WHITE 
Score 
 
2 pieces 
Shape 
ROUND 
Size 
 
7mm 
Flavor 
 
Imprint Code 
 
25;222 
Contains 
     
 
 
 
 
 
 
 
 
  
  
 
 
 
 


232 
 
Packaging 
 
# 
Item Code 
Package Description 
 
Marketing Start Date 
Marketing End Date 
1 
NDC:51862-321- 
01 
100 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
 
01/01/2018 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA090097 
01/01/2018 
 
 
 
LIOTHYRONINE SODIUM   
liothyronine sodium tablet 
 
 
 
Product Information 
 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:51862-322 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
 
Ingredient Name 
 
Basis of Strength 
Strength 
Liothyronine Sodium (UNII: GCA9VV7D2N) (liothyronine - UNII:06LU7C9H1V) 
 
liothyronine 
50 ug 
 
 
Inactive Ingredients 
 
Ingredient Name 
 
Strength 
calcium sulfate, unspecified form (UNII: WAT0DDB505) 
 
  
microcrystalline cellulose (UNII: OP1R32D61U) 
 
  
hypromellose, unspecified (UNII: 3NXW29V3WO) 
 
  
talc (UNII: 7SEV7J4R1U) 
 
  
silicon dioxide (UNII: ETJ7Z6XBU4) 
 
  


233 
 
 
 
Product Characteristics 
 
Color 
WHITE 
Score 
 
2 pieces 
Shape 
ROUND 
Size 
 
7mm 
Flavor 
 
Imprint Code 
 
50;223 
Contains 
     
 
 
 
Packaging 
 
# 
Item Code 
Package Description 
 
Marketing Start Date 
Marketing End Date 
1 
NDC:51862-322- 
01 
100 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination 
Product 
 
01/01/2018 
 
 
 
Marketing Information 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA090097 
01/01/2018 
 
 
 
Labeler - Mayne Pharma (867220261) 
Establishment 
Name 
Address 
ID/FEI 
Business Operations 
Mayne 
Pharma 
Inc. 
 
867220261 ANALYSIS(51862-320, 51862-321, 51862-322) , MANUFACTURE(51862-320, 51862-321, 51862-322) 
, PACK(51862-320, 51862-321, 51862-322) , LABEL(51862-320, 51862-321, 51862-322) 
Revised: 4/2019  
Mayne Pharma 
 
 
 
 
 
 


234 
 
 
 
APPENDIX G 
CYTOMEL- LIOTHYRONINE SODIUM TABLET PFIZER 
LABORATORIES DIV PFIZER INC 
---------- 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use CYTOMEL safely and effectively. See full 
prescribing information for CYTOMEL. 
CYTOMEL® (liothyronine sodium) tablets, for oral use 
Initial U.S. Approval: 1956 
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS 
See full prescribing information for complete boxed warning. 
Thyroid hormones, including CYTOMEL, should not be used for the treatment of obesity or for weight loss. 
Doses beyond the range of daily hormonal requirements may produce serious or even life-threatening 
manifestations of toxicity (6, 7.7, 10). 
 
 
 
Indications and Usage (1.1, 1.2, 1.3) 
RECENT MAJOR CHANGES 
12/2018 
 
Dosage and Administration (2.1, 2.2, 2.3, 2.4, 2.5, 2.6) 
12/2018 
Contraindications (4) 
12/2018 
Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6) 
12/2018 
 
 
 
INDICATIONS AND USAGE 
 
CYTOMEL is an L-triiodothyronine (T3) indicated for: 
Hypothyroidism: As replacement in primary (thyroidal), secondary (pituitary), and tertiary 
(hypothalamic) congenital or acquired hypothyroidism (1.1) 
Pituitary Thyroid-Stimulating Hormone (TSH) Suppression: As an adjunct to surgery and 
radioiodine therapy in the management of well-differentiated thyroid cancer (1.2) 
Thyroid Suppression Test: As a diagnostic agent in suppression tests to differentiate suspected 
mild hyperthyroidism or thyroid gland autonomy (1.3) 
Limitations of Use: 
- 
Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in iodine-sufficient 
patients. (1) 


235 
 
- 
Not indicated for treatment of hypothyroidism during the recovery phase of subacute thyroiditis. (1) 
DOSAGE AND ADMINISTRATION 
Administer CYTOMEL orally once daily and individual dosage according to patient response and 
laboratory findings 
(2.1) 
See full prescribing information for recommended dosage for hypothyroidism (2.2) TSH suppression 
in welldifferentiated thyroid cancer (2.3) and for thyroid suppression test (2.4) 
When switching a patient to CYTOMEL, discontinue levothyroxine therapy and initiate CYTOMEL at 
a low dosage. Gradually increase the dose according to the patient's response (2.5) 
Adequacy of therapy determined with periodic monitoring of TSH and T3 levels as well as clinical 
status (2.6) 
DOSAGE FORMS AND STRENGTHS 
Tablets: 5 mcg, 25 mcg, 50 mcg (3) 
CONTRAINDICATIONS 
Uncorrected adrenal cortical insufficiency (4) 
WARNINGS AND PRECAUTIONS 
Cardiac adverse reactions in the elderly and in patients with underlying cardiovascular disease: 
Initiate CYTOMEL at less than the full replacement dose because of the increased risk of cardiac 
adverse reactions, including atrial fibrillation (2.3, 5.1, 8.5) 
Myxedema coma: Do not use oral thyroid hormone drug products to treat myxedema coma. (5.2) 
Acute adrenal crisis in patients with concomitant adrenal insufficiency: Treat with replacement 
glucocorticoids prior to initiation of CYTOMEL treatment (5.3) 
Prevention of hyperthyroidism or incomplete treatment of hypothyroidism: Proper dose titration and 
careful monitoring is critical to prevent the persistence of hypothyroidism or the development of 
hyperthyroidism. (5.4) Worsening of diabetic control: Therapy in patients with diabetes mellitus may 
worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Carefully 
monitor glycemic control after starting, changing, or discontinuing thyroid hormone therapy (5.5) 
 Decreased bone mineral density associated with thyroid hormone over-replacement: Over-
replacement can increase bone resorption and decrease bone mineral density. Give the lowest 
effective dose (5.6) 
 
Most common adverse reactions for CYTOMEL are primarily those of hyperthyroidism due to 
therapeutic overdosage: arrhythmias, myocardial infarction, dyspnea, headache, nervousness, 
irritability, insomnia, tremors, muscle weakness, increased appetite, weight loss, diarrhea, heat 
intolerance, menstrual irregularities, and skin rash (6) 
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA1088 or 
www.fda.gov/medwatch. 
 
See full prescribing information for drugs that affect thyroid hormone pharmacokinetics and metabolism 
(e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and 
may alter the therapeutic response to 
CYTOMEL (7) 
 
Pregnancy may require the use of higher doses of thyroid hormone (2.2, 8.1) 
See 17 for PATIENT COUNSELING INFORMATION. 
Revised: 7/2019 
 
 
 


236 
 
 
FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: NOT FOR TREATMENT OF 
OBESITY OR FOR WEIGHT LOSS 1 INDICATIONS AND USAGE 
1.1 Hypothyroidism 
1.2 Pituitary Thyroid-Stimulating Hormone(TSH) Suppression 
1.3 Thyroid Suppression Test 
2 DOSAGE AND ADMINISTRATION 
2.1 General Principles of Dosing 
2.2 Recommended Dosage for Hypothyroidism 
2.3 Recommended Dosage for TSH Suppression in Well-Differentiated Thyroid Cancer 
2.4 Recommended Dosage for Thyroid Suppression Test 
2.5 Switching from Levothyroxine to CYTOMEL 
2.6 Monitoring TSH and Triiodothyronine (T3) Levels 
3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND 
PRECAUTIONS 
5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying 
Cardiovascular Disease 
5.2 Myxedema Coma 
5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency 
5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism 
5.5 Worsening of Diabetic Control 
5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-
Replacement 
6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics 
7.2 Antidiabetic Therapy 
7.3 Oral Anticoagulants 
7.4 Digitalis Glycosides 
7.5 Antidepressant Therapy 
7.6 Ketamine 
7.7 Sympathomimetics 
7.8 Tyrosine-Kinase Inhibitors 
7.9 Drug-Laboratory Test 
Interactions  


237 
 
8 USE IN SPECIFIC   
POPULATIONS 
8.1 Pregnancy 
8.2 Lactation 
8.4 Pediatric Use 
8.5 
Geriatric 
Use  
10 
OVERDO
SAGE 
11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
12.2 Pharmacodynamics 
12.3 Pharmacokinetics 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, 
Impairment of Fertility  
16 HOW SUPPLIED/STORAGE AND HANDLING 
17 PATIENT COUNSELING INFORMATION 
* Sections or subsections omitted from the full prescribing information are not listed. 
 
FULL PRESCRIBING INFORMATION 
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS 
Thyroid hormones, including CYTOMEL, either alone or with other therapeutic agents, 
should not be used for the treatment of obesity or for weight loss. 
In euthyroid patients, doses within the range of daily hormonal requirements are 
ineffective for weight reduction. 
Larger doses may produce serious or even life-threatening manifestations of toxicity, 
particularly when given in association with sympathomimetic amines such as those used for 
their anorectic effects [see Adverse Reactions (6), Drug Interactions (7.7), and Overdosage 
(10)]. 


238 
 
1 INDICATIONS AND USAGE 
1.1 Hypothyroidism 
CYTOMEL is indicated as a replacement therapy in primary (thyroidal), secondary 
(pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism. 
1.2 Pituitary Thyroid-Stimulating Hormone(TSH) Suppression 
CYTOMEL is indicated as an adjunct to surgery and radioiodine therapy in the 
management of welldifferentiated thyroid cancer. 
1.3 Thyroid Suppression Test 
CYTOMEL is indicated as a diagnostic agent in suppression tests to differentiate suspected 
mild hyperthyroidism or thyroid gland autonomy. 
Limitations of Use 
CYTOMEL is not indicated for suppression of benign thyroid nodules and nontoxic 
diffuse goiter in iodine-sufficient patients as there are no clinical benefits and 
overtreatment with CYTOMEL may induce hyperthyroidism [see Warnings and 
Precautions (5.4)]. 
CYTOMEL is not indicated for treatment of hypothyroidism during the recovery phase of 
subacute thyroiditis. 
2 DOSAGE AND ADMINISTRATION 
2.1 General Principles of Dosing 
The dose of CYTOMEL for hypothyroidism or pituitary TSH suppression depends on a 
variety of factors including: the patient's age, body weight, cardiovascular status, 
concomitant medical conditions (including pregnancy), concomitant medications, co-
administered food and the specific nature of the condition being treated [see Dosage 
and Administration (2.2, 2.3, 2.4), Warnings and Precautions (5), and Drug Interactions 
(7)]. Dosing must be individualized to account for these factors and dose adjustments 
made based on periodic assessment of the patient's clinical response and laboratory 
parameters [see Dosage and Administration (2.4)]. 
Administer CYTOMEL tablets orally once daily. 
2.2 Recommended Dosage for Hypothyroidism 
Adults 


239 
 
The recommended starting dosage is 25 mcg orally once daily. Increase the dose by 25 mcg 
daily every 1 or 2 weeks, if needed. The usual maintenance dose is 25 mcg to 75 mcg once 
daily. 
For elderly patients or patients with underlying cardiac disease, start with CYTOMEL 5 mcg 
once daily and increase by 5 mcg increments at the recommended intervals. 
Serum TSH is not a reliable measure of CYTOMEL dose adequacy in patients with 
secondary or tertiary hypothyroidism and should not be used to monitor therapy. Use 
the serum T3 level to monitor adequacy of therapy in this patient population. 
Pediatric Patients 
The recommended starting dosage is 5 mcg once daily, with a 5 mcg increase every 3 to 4 
days until the desired response is achieved. Infants a few months old may require 20 mcg 
once daily for maintenance. At 1 year of age, 50 mcg once daily may be required. Above 3 
years of age, the full adult dosage may be necessary [see Use in Specific Populations (8.4)]. 
Newborns (0 to 3 months) at Risk for Cardiac Failure: 
Consider a lower starting dose in infants at risk for cardiac failure. Increase the dose as 
needed based on clinical and laboratory response. 
Pediatric Patients at Risk for Hyperactivity: 
To minimize the risk of hyperactivity in pediatric patients, start at one-fourth the 
recommended full replacement dose, and increase on a weekly basis by one-fourth the full 
recommended replacement dose until the full recommended replacement dose is reached. 
Pregnancy 
Pre-existing Hypothyroidism: Thyroid hormone dose requirements may increase during 
pregnancy. Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at 
minimum, during each trimester of pregnancy. In patients with primary hypothyroidism, 
maintain serum TSH in the trimesterspecific reference range. For patients with serum 
TSH above the normal trimester-specific range, increase the dose of thyroid hormone 
and measure TSH every 4 weeks until a stable dose is reached and serum TSH is within 
the normal trimester-specific range. Reduce thyroid hormone dosage to prepregnancy 
levels immediately after delivery and measure serum TSH levels 4 to 8 weeks 
postpartum to ensure thyroid hormone dose is appropriate. 
2.3 Recommended Dosage for TSH Suppression in Well-Differentiated Thyroid Cancer 
The dose of CYTOMEL should target TSH levels within the desired therapeutic range. This 
may require higher doses, depending on the target level for TSH suppression. 


240 
 
2.4 Recommended Dosage for Thyroid Suppression Test 
The recommended dose is 75 mcg to 100 mcg daily for 7 days, with radioactive iodine 
uptake being determined before and after the 7 day administration of CYTOMEL. If 
thyroid function is normal, the radioiodine uptake will drop significantly after 
treatment. A 50% or greater suppression of uptake indicates a normal thyroid-
pituitary axis. 
2.5 Switching from Levothyroxine to CYTOMEL 
CYTOMEL has a rapid onset of action and residual effects of the other thyroid preparation 
may persist for the first several weeks after initiating CYTOMEL therapy. When switching 
a patient to CYTOMEL, discontinue levothyroxine therapy and initiate CYTOMEL at a low 
dosage. Gradually increase the CYTOMEL dose according to the patient's response. 
2.6 Monitoring TSH and Triiodothyronine (T3) Levels 
Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical 
evaluation. Persistent clinical and laboratory evidence of hypothyroidism despite an 
apparent adequate replacement dose of CYTOMEL may be evidence of inadequate 
absorption, poor compliance, drug interactions, or a combination of these factors. 
Adults 
In adult patients with primary hypothyroidism, monitor serum TSH periodically after 
initiation of the therapy or any change in dose. To check the immediate response to 
therapy before the TSH has had a 
chance to respond or if your patient's status needs to be assessed prior to that point, 
measurement of total T3 would be most appropriate. In patients on a stable and 
appropriate replacement dose, evaluate clinical and biochemical response every 6 to 12 
months and whenever there is a change in the patient's clinical status. 
Pediatrics 
In pediatric patients with hypothyroidism, assess the adequacy of replacement therapy by 
measuring serum TSH and T3 levels. For pediatric patients three years of age and older, 
the recommended monitoring is every 3 to 12 months thereafter, following dose 
stabilization until growth and puberty are completed. Poor compliance or abnormal values 
may necessitate more frequent monitoring. Perform routine clinical examination, 
including assessment of development, mental and physical growth, and bone maturation, 
at regular intervals. 
While the general aim of therapy is to normalize the serum TSH level, TSH may not 
normalize in some patients due to in utero hypothyroidism causing a resetting of pituitary-
thyroid feedback. Failure of the serum TSH to decrease below 20 IU per liter after initiation 
of CYTOMEL therapy may indicate the child is not receiving adequate therapy. Assess 


241 
 
compliance, dose of medication administered, and method of administration prior to 
increasing the dose of CYTOMEL [see Warnings and Precautions (5.1) and Use in Specific 
Populations (8.4)]. 
Secondary and Tertiary Hypothyroidism 
Monitor serum T3 levels and maintain in the normal range. 
3 DOSAGE FORMS AND STRENGTHS 
Tablets (round, white to off-white) available as follows: 
5 mcg: debossed with KPI on one side and 115 on the other side 
25 mcg: scored on one side and debossed with KPI and 116 on the other side 
50 mcg: scored on one side and debossed with KPI and 117 on the other side 
4 CONTRAINDICATIONS 
CYTOMEL is contraindicated in patients with uncorrected adrenal insufficiency [see 
Warnings and Precautions (5.3)]. 
5 WARNINGS AND PRECAUTIONS 
 5.1 CARDIAC ADVERSE REACTIONS IN THE ELDERLY AND IN PATIENTS WITH UNDERLYING 
CARDIOVASCULAR DISEASE 
Overtreatment with thyroid hormone may cause an increase in heart rate, cardiac wall 
thickness, and cardiac contractility and may precipitate angina or arrhythmias, 
particularly in patients with cardiovascular disease and in elderly patients. Initiate 
CYTOMEL therapy in this population at lower doses than those recommended in younger 
individuals or in patients without cardiac disease [see Dosage and Administration (2.3) 
and Use in Specific Populations (8.5)]. 
Monitor for cardiac arrhythmias during surgical procedures in patients with coronary 
artery disease receiving suppressive CYTOMEL therapy. Monitor patients receiving 
concomitant CYTOMEL and sympathomimetic agents for signs and symptoms of coronary 
insufficiency. If cardiovascular symptoms develop or worsen, reduce or withhold the 
CYTOMEL dose for one week and restart at a lower dose. 


242 
 
5.2 Myxedema Coma 
Myxedema coma is a life-threatening emergency characterized by poor circulation and 
hypometabolism, and may result in unpredictable absorption of thyroid hormone from 
the gastrointestinal tract. Use of oral thyroid hormone drug products is not 
recommended to treat myxedema coma. Administer thyroid hormone products 
formulated for intravenous administration to treat myxedema coma. 
5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency 
Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid 
hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute 
adrenal crisis in patients with adrenal insufficiency. Treat patients with adrenal 
insufficiency with replacement glucocorticoids prior to initiating treatment with 
CYTOMEL [see Contraindications (4)]. 
5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism 
CYTOMEL has a narrow therapeutic index. Over- or undertreatment with CYTOMEL 
may have negative effects on growth and development, cardiovascular function, bone 
metabolism, reproductive function, cognitive function, emotional state, 
gastrointestinal function, and on glucose and lipid metabolism. Titrate the dose of 
CYTOMEL carefully and monitor response to titration to avoid these effects [see 
Dosage and Administration (2.4)]. Monitor for the presence of drug or food 
interactions when using CYTOMEL and adjust the dose as necessary [see Drug 
Interactions (7) and Clinical Pharmacology (12.3)]. 
5.5 Worsening of Diabetic Control 
Addition of thyroid hormone therapy in patients with diabetes mellitus may worsen 
glycemic control and result in increased antidiabetic agent or insulin requirements. 
Carefully monitor glycemic control after starting, changing, or discontinuing CYTOMEL [see 
Drug Interactions (7.2)].  
5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-
Replacement 
Increased bone resorption and decreased bone mineral density may occur as a result of 
thyroid hormone over-replacement, particularly in post-menopausal women. 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. Administer the minimum dose of 
CYTOMEL that achieves the desired clinical and biochemical response to mitigate against 
this risk. 


243 
 
6 ADVERSE REACTIONS 
Adverse reactions associated with CYTOMEL therapy are primarily those of 
hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5.4) and 
Overdosage (10)]. 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 and cramps 
Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, 
heart failure, angina, myocardial infarction, cardiac arrest 
Respiratory: dyspnea 
Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests 
Dermatologic: hair loss, flushing 
Endocrine: decreased bone mineral density 
Reproductive: menstrual irregularities, impaired fertility 
Adverse Reactions in Pediatric Patients 
Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in 
pediatric patients receiving thyroid replacement therapy. Overtreatment may result in 
craniosynostosis in infants and premature closure of the epiphyses in pediatric 
patients with resultant compromised adult height. 
Hypersensitivity Reactions 
Hypersensitivity reactions to inactive ingredients have occurred in patients treated 
with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, 
angioedema, various gastrointestinal symptoms (abdominal pain, nausea, vomiting 
and diarrhea), fever, arthralgia, serum sickness and wheezing. 
7 DRUG INTERACTIONS 
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics 
Many drugs can exert effects on thyroid hormone pharmacokinetics (e.g. absorption, 
synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter 
the therapeutic response to CYTOMEL (see Tables 1 – 4). 


244 
 
TABLE 1: DRUGS THAT MAY DECREASE T3 ABSORPTION (HYPOTHYROIDISM) 
Potential impact: Concurrent use may reduce the efficacy of CYTOMEL by binding and 
Table 2: Drugs That May Alter Triiodothyronine (T3) Serum Transport Without 
Affecting Free Thyroxine (FT4) Concentration (Euthyroidism) 
DRUG OR DRUG CLASS 
Effect 
Clofibr
ate 
Estroge
ncontai
ning 
oral 
contrac
eptives 
Estrogens (oral) These drugs may increase serum thyroxine-binding globulin (TBG) 
Heroin / 
concentration. 
Methadone 
5-
Fluorourac
il Mitotane 
Tamoxifen 
Androgens / 
Anabolic 
Steroids 
Asparaginase 
These drugs may decrease serum TBG concentration. 
Glucocorticoids 
Slow-Release 
Nicotinic Acid 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


245 
 
  
Salicylates inhibit binding of T4 and T3 to TBG and 
transthyretin. An Salicylates (>2 
initial increase in serum FT4 is followed by 
return of FT4 to normal g/day) 
levels with sustained therapeutic serum 
salicylate concentrations, although total T4 levels may decrease by as much as 
30%. 
Other drugs: 
These drugs may cause protein binding site displacement. Furosemide 
Carbamazepine has been shown to inhibit the protein binding of T4 
to TBG and 
Furosemide (>80 albumin, causing an increased free-T4 fraction in serum. 
Furosemide 
mg IV) competes for T4-binding sites on TBG, prealbumin, and albumin, 
so 
Heparin that a single high dose can acutely lower the total T4 level. 
Phenytoin 
Hydantoins Nonand carbamazepine reduce serum protein binding of 
thyroid hormones, 
Steroidal Antiand total and FT4 may be reduced by 20% to 40%, but 
most patients 
inflammatory have normal serum TSH levels and are clinically euthyroid. 
Closely 
Drugs monitor thyroid hormone 
parameters. 
- Fenamates 
Table 3: Drugs That May Alter Hepatic Metabolism of Thyroid Hormones 
Potential impact: Stimulation of hepatic microsomal drug-metabolizing 
enzyme activity may cause increased hepatic degradation of thyroid 
hormones, resulting in increased CYTOMEL requirements. 
DRUG OR DRUG CLASS 
Effect 
Phenobarbital has been shown to reduce the response to thyroxine. 
Phenobarbital increases L-thyroxine metabolism by inducing uridine 
5'-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 
Phenobarbital serum levels. Changes in thyroid status may occur if 
barbiturates are 
Rifampin added or withdrawn from patients being treated for 
hypothyroidism. Rifampin has been shown to 
accelerate the metabolism of thyroid hormones. 


246 
 
TABLE 4: DRUGS THAT MAY DECREASE CONVERSION OF T4 TO T3 
Potential impact: 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. 
DRUG OR DRUG CLASS 
Effect 
In patients treated with large doses of propranolol (>160 mg/day), T3 
Beta-adrenergic and T4 levels change, TSH levels remain normal, and 
patients are 
antagonists (e.g., clinically euthyroid. Actions of particular beta-adrenergic  
antagonists 
Propranolol may be impaired when a hypothyroid patient is 
converted to the >160 mg/day) euthyroid state  
Short-term administration of large doses of glucocorticoids may 
Glucocorticoids decrease serum T3 concentrations by 30% with 
minimal change in (e.g., serum T4 levels. However, 
long-term glucocorticoid therapy may 
Dexamethasone result in slightly decreased T3 and T4 
levels due to decreased TBG ≥4 mg/day) production 
(see above). 
 
Amiodarone inhibits peripheral conversion of levothyroxine 
(T4) to Other drugs: triiodothyronine (T3) and may cause isolated biochemical 
changes 
Amiodarone 
(increase in serum free-T4, and decreased or normal free-T3) 
in clinically euthyroid patients. 
7.2 Antidiabetic Therapy 
Addition of CYTOMEL therapy in patients with diabetes mellitus may worsen glycemic 
control and result in increased antidiabetic agent or insulin requirements. Carefully 
monitor glycemic control, especially when CYTOMEL is started, changed, or discontinued 
[see Warnings and Precautions (5.5)]. 
7.3 Oral Anticoagulants 
CYTOMEL 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 


247 
 
when the CYTOMEL dose is increased. Closely monitor coagulation tests to permit 
appropriate and timely dosage adjustments. 
7.4 Digitalis Glycosides 
CYTOMEL may reduce the therapeutic effects of digitalis glycosides. Serum digitalis 
glycoside levels may be decreased when a hypothyroid patient becomes euthyroid, 
necessitating an increase in the dose of digitalis glycosides. 
7.5 Antidepressant Therapy 
Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) 
antidepressants and CYTOMEL 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 central nervous system stimulation. 
CYTOMEL may accelerate the onset of action of tricyclics. Administration of sertraline in 
patients stabilized on CYTOMEL may result in increased CYTOMEL requirements. 
7.6 Ketamine 
Concurrent use of ketamine and CYTOMEL may produce marked hypertension and 
tachycardia. Closely monitor blood pressure and heart rate in these patients. 
7.7 Sympathomimetics 
Concurrent use of sympathomimetics and CYTOMEL 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. 
7.8 Tyrosine-Kinase Inhibitors 
Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. 
Closely monitor TSH levels in such patients. 
7.9 Drug-Laboratory Test Interactions 
Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and 
evaluate unbound (free) hormone in this circumstance. Pregnancy, infectious hepatitis, 
estrogens, estrogencontaining oral contraceptives, and acute intermittent porphyria 
increase TBG concentrations. Nephrosis, severe hypoproteinemia, severe liver disease, 
acromegaly, androgens and corticosteroids decrease TBG concentration. Familial hyper- 
or hypo-thyroxine binding globulinemias have been described, with the incidence of TBG 
deficiency approximating 1 in 9000. 


248 
 
11 8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
Risk Summary 
Experience with liothyronine use in pregnant women, including data from post-marketing 
studies, have not reported increased rates of major birth defects or miscarriages (see 
Data). There are risks to the mother and fetus associated with untreated hypothyroidism 
in pregnancy. Since TSH levels may increase during pregnancy, TSH should be monitored 
and CYTOMEL dosage adjusted during pregnancy (see Clinical Considerations). There are 
no animal studies conducted with liothyronine during pregnancy. CYTOMEL should not be 
discontinued during pregnancy and hypothyroidism diagnosed during pregnancy should be 
promptly treated. 
The estimated background risk of major birth defects and miscarriage for the indicated 
population is unknown. In the U.S. general population, the estimated background risk 
of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% 
and 15 to 20%, respectively. 
Clinical Considerations 
Disease-associated maternal and/or embryo/fetal risk 
Maternal hypothyroidism during pregnancy is associated with a higher rate of 
complications, including spontaneous abortion, gestational hypertension, pre-eclampsia, 
stillbirth, and premature delivery. Untreated maternal hypothyroidism may have an 
adverse effect on fetal neurocognitive development. 
Dose adjustments during pregnancy and the postpartum period 
Pregnancy may increase CYTOMEL requirements. Serum TSH levels should be 
monitored and the CYTOMEL dosage adjusted during pregnancy. Since postpartum 
TSH levels are similar to preconception values, the CYTOMEL dosage should return to 
the pre-pregnancy dose immediately after delivery [see Dosage and Administration 
(2.3)]. 
Data 
Human Data 
Liothyronine is approved for use as a replacement therapy for hypothyroidism. Data 
from postmarketing studies have not reported increased rates of fetal 
malformations, miscarriages, or other adverse maternal or fetal outcomes 
associated with liothyronine use in pregnant women. 
8.2 Lactation 


249 
 
Risk Summary 
Limited published studies report that liothyronine is present in human milk. However, 
there is insufficient information to determine the effects of liothyronine on the breastfed 
infant and no available information on the effects of liothyronine on milk production. The 
developmental and health benefits of breastfeeding should be considered along with the 
mother's clinical need for CYTOMEL and any potential adverse effects on the breastfed 
infant from CYTOMEL or from the underlying maternal condition. 
8.4 Pediatric Use 
The initial dose of CYTOMEL varies with age and body weight. Dosing adjustments are 
based on an assessment of the individual patient's clinical and laboratory parameters [see 
Dosage and Administration (2.3, 2.4)]. 
In pediatric patients in whom a diagnosis of permanent hypothyroidism has not been 
established, discontinue thyroid hormone for a trial period, but only after the child is at 
least 3 years of age. Obtain serum TSH, T4, and T3 levels at the end of the trial period, and 
use laboratory test results and clinical assessments to guide diagnosis and treatment, if 
warranted [see Dosage and Administration (2.6)]. 
Congenital Hypothyroidism [see Dosage and Administration (2.2, 2.6)] 
Rapid restoration of normal serum T4 concentrations is essential for preventing the 
adverse effects of congenital hypothyroidism on intellectual development as well as on 
overall physical growth and maturation. Therefore, initiate thyroid hormone immediately 
upon diagnosis. Thyroid hormone is generally continued for life in these patients. 
Closely monitor infants during the first 2 weeks of thyroid hormone therapy for cardiac 
overload, arrhythmias, and aspiration from avid suckling. 
Closely monitor patients to avoid undertreatment or overtreatment. Undertreatment may 
have deleterious effects on intellectual development and linear growth. Overtreatment is 
associated with craniosynostosis in infants, may adversely affect the tempo of brain 
maturation, and may accelerate the bone age and result in premature epiphyseal closure 
and compromised adult stature [see Dosage and Administration (2.6) and Adverse Reactions 
(6)]. 
Acquired Hypothyroidism in Pediatric Patients 
Closely monitor patients to avoid undertreatment and overtreatment. Undertreatment may 
result in poor school performance due to impaired concentration and slowed mentation 
and in reduced adult height. Overtreatment may accelerate the bone age and result in 
premature epiphyseal closure and compromised adult stature. 
Treated children may manifest a period of catch-up growth, which may be adequate in 
some cases to normalize adult height. In children with severe or prolonged hypothyroidism, 
catch-up growth may not be adequate to normalize adult height [see Adverse Reactions 
(6)]. 


250 
 
8.5 Geriatric Use 
Because of the increased prevalence of cardiovascular disease among the elderly, initiate 
CYTOMEL at less than the full replacement dose [see Dosage and Administration (2.3) and 
Warnings and Precautions (5.1)]. Atrial arrhythmias can occur in elderly patients. Atrial 
fibrillation is the most common of the arrhythmias observed with thyroid hormone 
overtreatment in the elderly. 
10 OVERDOSAGE 
The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and 
Precautions (5.4) and Adverse Reactions (6)]. In addition, confusion and disorientation may 
occur. Cerebral embolism, seizure, shock, coma, and death have been reported. Symptoms 
may not necessarily be evident or may not appear until several days after ingestion. 
Reduce the CYTOMEL dose or temporarily discontinued if signs or symptoms of overdosage 
occur. Initiate appropriate supportive treatment as dictated by the patient's medical status. 
For current information on the management of poisoning or overdosage, contact the 
National Poison Control Center at 1-800-222-1222 or www.poison.org. 
11 DESCRIPTION 
CYTOMEL tablets contain the active ingredient, liothyronine (L-triiodothyronine or LT3), a 
synthetic form of a thyroid hormone liothyronine in sodium salt form. It is chemically 
designated as L-Tyrosine, O-(4-hydroxy-3-iodophenyl)-3,5-diiodo-, monosodium salt. The 
molecular formula, molecular weight and structural formula of liothyronine sodium are 
given below. 
 
CYTOMEL tablets contain liothyronine sodium equivalent to liothyronine in 5 mcg, 25 mcg, 
and 50 mcg. Inactive ingredients consist of calcium sulfate, corn starch, gelatin, stearic acid, 
sucrose and talc. 


251 
 
12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
Thyroid hormones exert their physiologic actions through control of DNA transcription and 
protein synthesis. Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell nucleus 
and bind to thyroid receptor proteins attached to DNA. This hormone nuclear receptor 
complex activates gene transcription and synthesis of messenger RNA and cytoplasmic 
proteins. 
The physiological actions of thyroid hormones are produced predominantly by T3, the 
majority of which (approximately 80%) is derived from T4 by deiodination in peripheral 
tissues. 
12.2 Pharmacodynamics 
The onset of activity of liothyronine sodium occurs within a few hours. Maximum 
pharmacologic response occurs within 2 or 3 days. 
12.3 Pharmacokinetics 
Absorption 
T3 is almost totally absorbed, 95 percent in 4 hours. The hormones contained in the natural 
preparations are absorbed in a manner similar to the synthetic hormones. 
Distribution 
Liothyronine sodium (T3) is not firmly bound to serum protein. The higher affinity of 
levothyroxine 
(T4) for both thyroid-binding globulin and thyroid-binding prealbumin as compared to 
triiodothyronine (T3) partially explains the higher serum levels and longer half-life of the 
former hormone. Both protein-bound hormones exist in reverse equilibrium with minute 
amounts of free hormone, the latter accounting for the metabolic activity. 
Elimination 
Metabolism 
The major pathway of thyroid hormone metabolism is through sequential deiodination. 
Approximately 80% of circulating T3 is derived from peripheral T4 by monodeiodination. 
The liver is the major site of degradation for both T4 and T3. T3 is further deiodinated to 
diiodothyronine. Thyroid hormones are also metabolized via conjugation with 
glucuronides and sulfates and excreted directly into the bile and gut where they undergo 
enterohepatic recirculation. 
Excretion 


252 
 
Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated 
hormone reaches the colon unchanged and is eliminated in the feces. The biological half-
life is about 2–1/2 days. 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
Animal studies have not been performed to evaluate the carcinogenic potential, 
mutagenic potential or effects on fertility of liothyronine sodium. 
16 HOW SUPPLIED/STORAGE AND HANDLING 
CYTOMEL tablets (round, white to off-white) are supplied as follows: 
 
17 PATIENT COUNSELING INFORMATION 
Dosing and Administration 
Instruct patients that CYTOMEL should only be taken as directed by their healthcare 
provider. Instruct patients to notify their healthcare provider should they become 
pregnant or breastfeeding or are thinking of becoming pregnant, while taking CYTOMEL. 
Important Information 
Inform patients that the liothyronine in CYTOMEL is intended to replace a hormone that 
is normally produced by the thyroid gland. Generally replacement therapy is to be 
taken for life. 
Inform patients that CYTOMEL should not be used as a primary or adjunctive therapy in 
a weight control program. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Store between 15°C and 30°C (59°F and 86°F). 


253 
 
Instruct patients to notify their healthcare provider if they are taking any other 
medications, including prescription and over-the-counter preparations. 
Instruct patients to notify their healthcare provider of any other medical conditions, 
particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland 
problems, as the dose of medications used to control these other conditions may need to 
be adjusted while taking CYTOMEL. If patents are taking anticoagulants (blood thinners), 
their clotting status should be checked frequently. 
 Instruct patients to notify their physician or dentist if they are taking CYTOMEL prior to 
any surgery. 
Adverse Reactions 
 Instruct patients to notify their healthcare provider if they experience any of the 
following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, leg 
cramps, headache, nervousness, irritability, sleeplessness, tremors, change in 
appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat 
intolerance, fever, changes in menstrual periods, hives or skin rash, or any other 
unusual medical event [see Adverse Reactions (6)]. 
 Inform patients that partial hair loss may occur rarely during the first few months of 
CYTOMEL therapy; this is usually temporary [see Adverse Reactions (6)]. 
This product's label may have been updated. For current full prescribing information, please 
visit www.pfizer.com. 
 
LAB-0683-5.0 
PRINCIPAL DISPLAY PANEL - 5 MCG TABLET BOTTLE LABEL 
NDC 60793-115-01 
Pfizer 
CYTOMEL®  
liothyronine sodium tablets 
5 mcg 
100 Tablets RX only 


254 
 
 
PRINCIPAL DISPLAY PANEL - 25 MCG TABLET BOTTLE LABEL 
NDC 60793-116-01 
Pfizer 
CYTOMEL®  
liothyronine sodium tablets 
25 mcg 
100 Tablets RX only 
RX ONLY 
 
PRINCIPAL DISPLAY PANEL - 50 MCG TABLET BOTTLE LABEL 
NDC 60793-117-01 
Pfizer 


255 
 
CYTOMEL®  
liothyronine sodium tablets 
50 mcg5 mcg 
100 Tablets RX only 
 
 
CYTOMEL   
liothyronine sodium tablet 
 
Product Information 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:60793-115 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
Ingredient Name 
Basis of Strength 
Strength 
LIOTHYRONINE SODIUM (UNII: GCA9VV7D2N) (LIOTHYRONINE - UNII:06LU7C9H1V) 
LIOTHYRONINE 
5 ug 
 
Product Characteristics 
Color 
WHITE (white to off-white) 
Score 
no score 
Shape 
ROUND 
Size 
6mm 


256 
 
Flavor 
 
Imprint Code 
KPI;115 
Contains 
     
 
 
Packaging 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:60793-115-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 
05/08/1956 
 
 
Marketing Information 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
NDA 
NDA010379 
05/08/1956 
 
 
CYTOMEL   
liothyronine sodium tablet 
 
 
Product Information 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:60793-116 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
Ingredient Name 
Basis of Strength 
Strength 
LIOTHYRONINE SODIUM (UNII: GCA9VV7D2N) (LIOTHYRONINE - UNII:06LU7C9H1V) 
LIOTHYRONINE 
25 ug 
 
Product Characteristics 
Color 
WHITE (white to off-white) 
Score 
2 pieces 
Shape 
ROUND 
Size 
7mm 
Flavor 
 
Imprint Code 
KPI;116 


257 
 
Contains 
     
 
 
Packaging 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:60793-116-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 
05/08/1956 
 
 
Marketing Information 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
NDA 
NDA010379 
05/08/1956 
 
 
CYTOMEL   
liothyronine sodium tablet 
 
Product Information 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:60793-117 
Route of Administration 
ORAL 
 
 
Active Ingredient/Active Moiety 
Ingredient Name 
Basis of Strength 
Strength 
LIOTHYRONINE SODIUM (UNII: GCA9VV7D2N) (LIOTHYRONINE - UNII:06LU7C9H1V) 
LIOTHYRONINE 
50 ug 
 
Product Characteristics 
Color 
WHITE (white to off-white) 
Score 
2 pieces 
Shape 
ROUND 
Size 
8mm 
Flavor 
 
Imprint Code 
KPI;117 
Contains 
     
 
 


258 
 
 
Packaging 
 
 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:60793-117-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 
05/08/1956 
 
 
 
 
Marketing Information 
 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
NDA 
NDA010379 
05/08/1956 
 
 
 
 
Labeler - Pfizer Laboratories Div Pfizer Inc (134489525) 
Establishment 
 
 
 
Name 
Address 
ID/FEI 
Business Operations 
Peptido GmbH 
 
327335410 
API MANUFACTURE(60793-115) 
Revised: 7/2019  
Pfizer Laboratories Div Pfizer Inc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


259 
 
APPENDIX H 
LIOTHYRONINE SODIUM- LIOTHYRONINE SODIUM TABLET  
SIGMAPHARM LABORATORIES, LLC 
---------- 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use LIOTHYRONINE 
SODIUM TABLETS, USP safely and effectively. See full prescribing information for 
LIOTHYRONINE SODIUM TABLETS, USP.  
LIOTHYRONINE SODIUM TABLETS, USP, for oral use  
Initial U.S. Approval: 1956 
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS  
See full prescribing information for complete boxed warning. 
Thyroid hormones, including liothyronine sodium should not be used for the treatment of 
obesity or for weight loss. 
Doses beyond the range of daily hormonal requirements may produce serious or even life-
threatening manifestations of toxicity ( 6, 7.7, 10) 
 
 
 
Indications and Usage ( 1.1, 1.2, 1.3) 
RECENT MAJOR 
CHANGES 
12/2018 
 
Dosage and Administration ( 2.1, 2.2, 2.3, 2.4, 2.5, 2.6) 
12/2018 
Contraindications ( 4) 
12/2018 
Warnings and Precautions ( 5.1, 5.2, 5.3, 5.4, 5.5, 5.6) 
12/2018 
 
 
 
INDICATIONS AND 
USAGE 
 
Liothyronine sodium is an L-triiodothyronine (T3) indicated for: 
Hypothyroidism: As replacement in primary (thyroidal), secondary (pituitary), and 
tertiary (hypothalamic) congenital or acquired hypothyroidism ( 1.1) 
 
 


260 
 
Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression: As an adjunct to 
surgery and radioiodine therapy in the management of well-differentiated thyroid 
cancer ( 1.2) 
Thyroid Suppression Test: As a diagnostic agent in suppression tests to differentiate 
suspected mild hyperthyroidism or thyroid gland autonomy ( 1.3) 
Limitations of Use:  
- Not indicated for suppression of benign thyroid nodules and nontoxic diffuse goiter in 
iodine-sufficient patients. ( 1)  
- Not indicated for treatment of hypothyroidism during the recovery phase of subacute 
thyroiditis. ( 1) 
DOSAGE AND ADMINISTRATION 
Administer Liothyronine Sodium Tablets, USP orally once daily and individual dosage 
according to patient response and laboratory findings ( 2.1) 
See full prescribing information for recommended dosage for hypothyroidism ( 2.2) TSH 
suppression in welldifferentiated thyroid cancer ( 2.3) and for thyroid suppression test ( 
2.4) 
When switching a patient to Liothyronine Sodium Tablets, USP discontinue 
levothyroxine therapy and initiate 
Liothyronine Sodium Tablets, USP at a low dosage. Gradually increase the dose 
according to the patient's response ( 
2.5) 
Cardiac adverse reactions in the elderly and in patients with underlying cardiovascular 
disease: Initiate Liothyronine Sodium Tablets, USP at less than the full replacement dose 
because of the increased risk of cardiac adverse reactions, including atrial fibrillation ( 
2.3, 5.1, 8.5) 
Myxedema coma: Do not use oral thyroid hormone drug products to treat myxedema 
coma. ( 5.2) 
Acute adrenal crisis in patients with concomitant adrenal insufficiency: Treat with 
replacement glucocorticoids prior to initiation of liothyronine sodium treatment ( 5.3) 
Prevention of hyperthyroidism or incomplete treatment of hypothyroidism: Proper 
dose titration and careful monitoring is critical to prevent the persistence of 
hypothyroidism or the development of hyperthyroidism. ( 5.4) Worsening of diabetic 
control: Therapy in patients with diabetes mellitus may worsen glycemic control and 
result in increased antidiabetic agent or insulin requirements. Carefully monitor 
glycemic control after starting, changing, or discontinuing thyroid hormone therapy ( 
5.5) 
  
 
Tablets: 5 mcg, 25 mcg, 50 mcg     
 
    
 


261 
 
 Decreased bone mineral density associated with thyroid hormone over-replacement: 
Over-replacement can increase bone resorption and decrease bone mineral density. 
Give the lowest effective dose ( 5.6) 
 
Most common adverse reactions for Liothyronine Sodium Tablets, USP are primarily 
those of hyperthyroidism due to therapeutic overdosage: arrhythmias, myocardial 
infarction, dyspnea, headache, nervousness, irritability, insomnia, tremors, muscle 
weakness, increased appetite, weight loss, diarrhea, heat intolerance, menstrual 
irregularities, and skin rash (6) 
To report SUSPECTED ADVERSE REACTIONS, contact Sigmapharm Laboratories, LLC, 
Pharmacovigilance at 1-855-332-0731 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch. (6) 
 
See full prescribing information for drugs that affect thyroid hormone pharmacokinetics 
and metabolism (e.g., absorption, synthesis, secretion, catabolism, protein binding, and 
target tissue response) and may alter the therapeutic response to liothyronine sodium 
(7) 
 
Pregnancy may require the use of higher doses of thyroid hormone ( 2.2, 8.1) 
See 17 for PATIENT COUNSELING INFORMATION. 
Revised: 8/2019 
 
FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: NOT FOR TREATMENT OF 
OBESITY OR FOR WEIGHT LOSS  
1 INDICATIONS AND USAGE 
1.1 Hypothyroidism  
1.2 Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression 
1.3 Thyroid Suppression Test 
2   DOSAGE AND ADMINISTRATION 
2.1 General Principles of Dosing  
2.2 Recommended Dosage for Hypothyroidism  
2.3 Recommended Dosage for TSH Suppression in Well-Differentiated Thyroid Cancer 
2.4 Recommended Dosage for Thyroid Suppression Test  
 
 
 


262 
 
2.5 Switching from Levothyroxine to Liothyronine Sodium Tablets, USP 
2.6 Monitoring TSH and Triiodothyronine (T3) Levels 
3 DOSAGE FORMS AND STRENGTHS  
4 CONTRAINDICATIONS  
5 WARNINGS AND PRECAUTIONS 
5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying 
Cardiovascular Disease 
 5.2 Myxedema Coma  
5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency  
5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism  
5.5 Worsening of Diabetic Control  
5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-
Replacement 
6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics 
7.2 Antidiabetic Therapy 
7.3 Oral Anticoagulants  
7.4 Digitalis Glycosides  
7.5 Antidepressant Therapy  
7.6 Ketamine  
7.7 Sympathomimetics 
 7.8 Tyrosine-Kinase Inhibitors  
7.9 Drug-Laboratory Test Interactions 
8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy  
8.2 Lactation  
8.4 Pediatric Use  
8.5 Geriatric Use 


263 
 
10 OVERDOSAGE  
11 DESCRIPTION  
12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action  
12.2 Pharmacodynamics  
12.3 Pharmacokinetics 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
16 HOW SUPPLIED/STORAGE AND 
HANDLING 
17 PATIENT COUNSELING INFORMATION 
* Sections or subsections omitted from the full prescribing information are not listed. 
 
FULL PRESCRIBING INFORMATION 
WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS 
Thyroid hormones, including liothyronine sodium, either alone or with other 
therapeutic agents, should not be used for the treatment of obesity or for weight loss. 
In euthyroid patients, doses within the range of daily hormonal requirements are 
ineffective for weight reduction. 
Larger doses may produce serious or even life-threatening manifestations of toxicity, 
particularly when given in association with sympathomimetic amines such as those used for 
their anorectic effects [see Adverse Reactions (6), Drug Interactions (7.7), and Overdosage 
(10)]. 


264 
 
1 INDICATIONS AND USAGE 
1.1 Hypothyroidism 
Liothyronine Sodium Tablets, USP are indicated as a replacement therapy in primary 
(thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired 
hypothyroidism. 
1.2 Pituitary Thyrotropin (Thyroid-Stimulating Hormone, TSH) Suppression 
Liothyronine Sodium Tablets, USP are indicated as an adjunct to surgery and radioiodine 
therapy in the management of well-differentiated thyroid cancer. 
1.3 Thyroid Suppression Test 
Liothyronine Sodium Tablets, USP are indicated as a diagnostic agent in suppression tests to 
differentiate suspected mild hyperthyroidism or thyroid gland autonomy. 
Limitations of Use 
 Liothyronine Sodium Tablets, USP are not indicated for suppression of benign thyroid 
nodules and nontoxic diffuse goiter in iodine-sufficient patients as there are no clinical 
benefits and overtreatment with Liothyronine Sodium Tablets, USP may induce 
hyperthyroidism [see Warnings and Precautions (5.4)]. 
 Liothyronine Sodium Tablets, USP are not indicated for treatment of hypothyroidism 
during the recovery phase of subacute thyroiditis. 
2   DOSAGE AND ADMINISTRATION 
2.1 General Principles of Dosing 
The dose of Liothyronine Sodium Tablets, USP for hypothyroidism or pituitary Thyroid-
Stimulating Hormone (TSH) suppression depends on a variety of factors including: the 
patient's age, body weight, cardiovascular status, concomitant medical conditions 
(including pregnancy), concomitant medications, co-administered food and the specific 
nature of the condition being treated [see Dosage 
and Administration (2.2, 2.3, 2.4), Warnings and Precautions (5), and Drug Interactions (7)] 
. Dosing must be individualized to account for these factors and dose adjustments made 
based on periodic assessment of the patient's clinical response and laboratory parameters 
[see Dosage and Administration (2.4)]. 
Administer Liothyronine Sodium Tablets, USP orally once daily. 
2.2 Recommended Dosage for Hypothyroidism 


265 
 
Adults  
The recommended starting dosage is 25 mcg orally once daily. Increase the dose by 25 mcg 
daily every 1 or 2 weeks, if needed. The usual maintenance dose is 25 mcg to 75 mcg once 
daily.  
For elderly patients or patients with underlying cardiac disease, start with Liothyronine 
Sodium Tablets, USP 5 mcg once daily and increase by 5 mcg increments at the 
recommended intervals.  
Serum TSH is not a reliable measure of liothyronine sodium dose adequacy in patients 
with secondary or tertiary hypothyroidism and should not be used to monitor therapy. 
Use the serum T3 level to monitor adequacy of therapy in this patient population. 
Pediatric Patients  
The recommended starting dosage is 5 mcg once daily, with a 5 mcg increase every 3 to 4 
days until the desired response is achieved. Infants a few months old may require 20 mcg 
once daily for maintenance. At 1 year of age, 50 mcg once daily may be required. Above 3 
years of age, the full adult dosage may be necessary [see Use in Specific Populations (8.4)]. 
Newborns (0 to 3 months) at Risk for Cardiac Failure:  
Consider a lower starting dose in infants at risk for cardiac failure. Increase the dose as 
needed based on clinical and laboratory response. 
Pediatric Patients at Risk for Hyperactivity:  
To minimize the risk of hyperactivity in pediatric patients, start at one-fourth the 
recommended full replacement dose, and increase on a weekly basis by one-
fourth the full recommended replacement dose until the full recommended 
Pregnancy  
Pre-existing Hypothyroidism: Thyroid hormone dose requirements may increase during 
pregnancy. Measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at 
minimum, during each trimester of pregnancy. In patients with primary hypothyroidism, 
maintain serum TSH in the trimester-specific reference range. For patients with serum TSH 
above the normal trimesterspecific range, increase the dose of thyroid hormone and 
measure TSH every 4 weeks until a stable dose is reached and serum TSH is within the 
normal trimester-specific range. Reduce thyroid hormone dosage to pre-pregnancy levels 
immediately after delivery and measure serum TSH levels 4 to 8 weeks postpartum to 
ensure thyroid hormone dose is appropriate. 
2.3 Recommended Dosage for TSH Suppression in Well-Differentiated Thyroid Cancer 
 


266 
 
 
The dose of Liothyronine Sodium Tablets, USP should target TSH levels within the desired 
therapeutic range. This may require higher doses, depending on the target level for TSH 
suppression. 
2.4 Recommended Dosage for Thyroid Suppression Test 
The recommended dose is 75 mcg to 100 mcg daily for 7 days, with radioactive iodine 
uptake being determined before and after the 7 day administration of Liothyronine 
Sodium Tablets, USP. If thyroid function is normal, the radioiodine uptake will drop 
significantly after treatment. A 50% or greater suppression of uptake indicates a 
normal thyroid-pituitary axis. 
2.5 Switching from Levothyroxine to Liothyronine Sodium Tablets, USP 
Liothyronine sodium has a rapid onset of action and residual effects of the other thyroid 
preparation may persist for the first several weeks after initiating liothyronine sodium 
therapy. When switching a patient to Liothyronine Sodium Tablets, USP, discontinue 
levothyroxine therapy and initiate Liothyronine Sodium Tablets, USP at a low dosage. 
Gradually increase the liothyronine sodium dose according to the patient's response. 
2.6 Monitoring TSH and Triiodothyronine (T3) Levels 
Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical 
evaluation. Persistent clinical and laboratory evidence of hypothyroidism despite an 
apparent adequate replacement dose of Liothyronine Sodium Tablets, USP may be 
evidence of inadequate absorption, poor compliance, drug interactions, or a combination 
of these factors. 
Adults  
In adult patients with primary hypothyroidism, monitor serum TSH periodically after 
initiation of the therapy or any change in dose. To check the immediate response to 
therapy before the TSH has had a chance to respond or if your patient's status needs to be 
assessed prior to that point, measurement of total T3 would be most appropriate. In 
patients on a stable and appropriate replacement dose, evaluate clinical and biochemical 
response every 6 to 12 months and whenever there is a change in the patient's clinical 
status. 
Pediatrics  
In pediatric patients with hypothyroidism, assess the adequacy of replacement therapy 
by measuring serum TSH and T3 levels. For pediatric patients three years of age and 
older, the recommended monitoring is every 3 to 12 months thereafter, following dose 
stabilization until growth and puberty are completed. Poor compliance or abnormal 


267 
 
values may necessitate more frequent monitoring. Perform routine clinical examination, 
including assessment of development, mental and physical growth, and bone 
maturation, at regular intervals. 
While the general aim of therapy is to normalize the serum TSH level, TSH may not 
normalize in some patients due to in utero hypothyroidism causing a resetting of pituitary-
thyroid feedback. Failure of the serum TSH to decrease below 20 IU per liter after 
initiation of liothyronine sodium therapy may indicate the child is not receiving adequate 
therapy. Assess compliance, dose of medication administered, and method of 
administration prior to increasing the dose of Liothyronine Sodium Tablets, USP [see 
Warnings and Precautions (5.1) andUse in Specific Populations (8.4)]. 
Secondary and Tertiary Hypothyroidism  
Monitor serum T3 levels and maintain in the normal range. 
3 DOSAGE FORMS AND STRENGTHS 
Tablets (white to off-white, round, SC) available as follows: 
5 mcg: debossed “∑” on one side and “18” on the other side 
25 mcg: debossed “∑19” on one side and “BISECTED” on the other side 
50 mcg: debossed “∑20” on one side and “BISECTED” on the other side 
4 CONTRAINDICATIONS 
Liothyronine Sodium Tablets, USP are contraindicated in patients with uncorrected adrenal 
insufficiency [see Warnings and Precautions (5.3)]. 
5 WARNINGS AND PRECAUTIONS 
5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying 
Cardiovascular Disease 
Overtreatment with thyroid hormone may cause an increase in heart rate, cardiac wall 
thickness, and cardiac contractility and may precipitate angina or arrhythmias, particularly 
in patients with cardiovascular disease and in elderly patients. Initiate liothyronine sodium 
therapy in this population at lower doses than those recommended in younger individuals 
or in patients without cardiac disease [see  Dosage and Administration (2.3) and Use in 
Specific Populations (8.5)]. 
Monitor for cardiac arrhythmias during surgical procedures in patients with coronary 
artery disease receiving suppressive liothyronine sodium therapy. Monitor patients 
receiving concomitant Liothyronine Sodium Tablets, USP and sympathomimetic agents 
for signs and symptoms of coronary insufficiency. If cardiovascular symptoms develop 


268 
 
or worsen, reduce or withhold the liothyronine sodium dose for one week and restart 
at a lower dose. 
5.2 Myxedema Coma 
Myxedema coma is a life-threatening emergency characterized by poor circulation and 
hypometabolism, and may result in unpredictable absorption of thyroid hormone from the 
gastrointestinal tract. Use of oral thyroid hormone drug products is not recommended to 
treat myxedema coma. Administer thyroid hormone products formulated for intravenous 
administration to treat myxedema coma. 
5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency 
Thyroid hormone increases metabolic clearance of glucocorticoids. Initiation of thyroid 
hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute 
adrenal crisis in patients with adrenal insufficiency. Treat patients with adrenal 
insufficiency with replacement glucocorticoids prior to initiating treatment with 
Liothyronine Sodium Tablets, USP [see Contraindications (4)]. 
5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism 
Liothyronine sodium has a narrow therapeutic index. Over- or undertreatment with 
liothyronine sodium may have negative effects on growth and development, 
cardiovascular function, bone metabolism, reproductive function, cognitive function, 
emotional state, gastrointestinal function, and on glucose and lipid metabolism. Titrate 
the dose of Liothyronine Sodium Tablets, USP carefully and monitor response to titration 
to avoid these effects [see Dosage and Administration (2.4)] . Monitor for the presence of 
drug or food interactions when using Liothyronine Sodium Tablets, USP and adjust the 
dose as necessary [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. 
5.5 Worsening of Diabetic Control 
Addition of thyroid hormone therapy in patients with diabetes mellitus may worsen 
glycemic control and result in increased antidiabetic agent or insulin requirements. 
Carefully monitor glycemic control after starting, changing, or discontinuing Liothyronine 
Sodium Tablets, USP  [see Drug Interactions (7.2)]. 
5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-
Replacement 
Increased bone resorption and decreased bone mineral density may occur as a result of 
thyroid hormone over-replacement, particularly in post-menopausal women. 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. Administer the minimum dose of Liothyronine Sodium Tablets, 
USP that achieves the desired clinical and biochemical response to mitigate against this risk. 


269 
 
6 ADVERSE REACTIONS 
Adverse reactions associated with liothyronine sodium therapy are primarily those of 
hyperthyroidism due to therapeutic overdosage [see Warnings and Precautions (5.4) 
and Overdosage (10)] . 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 and cramps  
Cardiovascular: palpitations, tachycardia, arrhythmias, increased pulse and blood pressure, 
heart failure, angina, myocardial infarction, cardiac arrest  
Respiratory: dyspnea  
Gastrointestinal: diarrhea, vomiting, abdominal cramps, elevations in liver function tests 
Dermatologic: hair loss, flushing  
Endocrine: decreased bone mineral density  
Reproductive: menstrual irregularities, impaired fertility  
Adverse Reactions in Pediatric Patients  
Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in 
pediatric patients receiving thyroid replacement therapy. Overtreatment may result in 
craniosynostosis in infants and premature closure of the epiphyses in pediatric patients 
with resultant compromised adult height.  
Hypersensitivity Reactions  
Hypersensitivity reactions to inactive ingredients have occurred in patients treated 
with thyroid hormone products. These include urticaria, pruritus, skin rash, flushing, 
angioedema, various gastrointestinal symptoms (abdominal pain, nausea, vomiting 
and diarrhea), fever, arthralgia, serum sickness and wheezing.  
To report SUSPECTED ADVERSE REACTIONS, contact Sigmapharm Laboratories, 
LLC, Pharmacovigilance at 1-855-332-0731 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch. 
7 DRUG INTERACTIONS 
7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics 
Many drugs can exert effects on thyroid hormone pharmacokinetics (e.g. 
absorption, synthesis, secretion, catabolism, protein binding, and target tissue 
response) and may alter the therapeutic response to liothyronine sodium (see 
Tables 1 - 4). 


270 
 
 
TABLE 1: DRUGS THAT MAY DECREASE T3 ABSORPTION (HYPOTHYROIDISM) 
 
 
Potential impact: Concurrent use may reduce the efficacy of liothyronine sodium by 
binding and delaying or preventing absorption, potentially resulting in hypothyroidism. 
 
 
Drug or Drug 
Class 
Effect 
Bile Acid 
Sequestrants 
-Colesevelam 
-Cholestyramine 
-Colestipol 
Ion Exchange 
Resins 
-Kayexalate 
-Sevelamer 
Bile acid sequestrants and ion exchange resins are known to decrease 
thyroid hormones absorption. Administer Liothyronine Sodium 
to these drugs or monitor TSH 
levels. 
 
 
Table 2: Drugs That May Alter Triiodothyronine (T 3) Serum Transport Without 
Affecting Free Thyroxine (FT 4) Concentration (Euthyroidism) 
 
 
Drug 
or 
Drug 
Class 
Effect 
Clofibrate 
Estrogencontaining 
oral 
contraceptives 
Estrogens (oral) 
Heroin / 
Methadone 
5-Fluorouracil 
Mitotane 
Tamoxifen 
These drugs may increase serum thyroxine-
binding globulin (TBG) 
concentration 
Androgens / 
Anabolic 
Steroids 
Asparaginase 
Glucocorticoids 
These 
drugs 
may 
decrease serum TBG 
concentration 


271 
 
Slow-Release 
Nicotinic Acid 
 
 
Salicylates (>2 
g/day) 
 
Salicylates inhibit binding of T4 and T3 to TBG 
and transthyretin. An initial increase in serum 
FT4 is followed by return of FT4 to normal 
levels with sustained therapeutic serum 
salicylate concentrations, although total T4 
levels may decrease by as much as 30%. 
Other drugs: 
Carbamazepine 
Furosemide  >80 
mg IV Heparin 
Hydantoins Non- 
Steroidal 
Antiinflammatory 
Drugs 
- Fenamates H 
These drugs may cause protein binding site 
displacement. Furosemide has been shown 
to inhibit the protein binding of T4 to TBG and 
albumin, causing an increased free-T4 
fraction in serum. Furosemide competes for 
T4-binding sites on TBG, prealbumin, and 
albumin, so 
that a single high dose can acutely lower the 
total T4 level. Phenytoin and carbamazepine 
reduce serum protein binding of thyroid 
hormones, and total and FT4 may be reduced 
by 20% to 40%, but most patients  
have normal serum TSH levels and are 
clinically euthyroid. Closely monitor thyroid 
hormone parameters 
 
 Table 3: Drugs That May Alter Hepatic Metabolism of Thyroid hormones 
  
 
 
Table 4: Drugs That May Decrease Conversion of T 4 to T 3 
 
 
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity 
may cause increased hepatic degradation of thyroid hormones, resulting in increased 
liothyronine sodium requirements. 
Drug or Drug 
Class 
Effect 
Phenobarbital 
Rifampin 
Phenobarbital has been shown to reduce the response to thyroxine. 
Phenobarbital increases L-thyroxine metabolism by inducing uridine 5'-
diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 
serum levels. Changes in thyroid status may occur if barbiturates are 
added or withdrawn from patients being treated for hypothyroidism.  
Rifampin has been shown to accelerate the metabolism of thyroid 
hormones


272 
 
Potential impact: 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. 
Drug or Drug 
Class 
Effect 
Beta-adrenergic 
antagonists (e.g., 
Propranolol 
>160 mg/day) 
In patients treated with large doses of propranolol (>160 mg/day), T3 
and T4 levels change, TSH levels remain normal, and patients are 
clinically euthyroid. Actions of particular beta-adrenergic antagonists 
may be impaired when a hypothyroid patient is converted to the 
euthyroid state. 
Glucocorticoids 
(e.g., 
Dexamethasone 
≥4 mg/day) 
Short-term administration of large doses of glucocorticoids may 
decrease serum T3 concentrations by 30% with minimal change in 
serum T4 levels. However, long-term glucocorticoid therapy may 
result in slightly decreased T3 and T4 levels due to decreased TBG 
production (see above). 
Other drugs: 
Amiodarone 
Amiodarone inhibits peripheral conversion of levothyroxine (T4) to 
triiodothyronine (T3) and may cause isolated biochemical changes 
(increase in serum free-T4, and decreased or normal free-T3) in 
clinically euthyroid patients. 
 
7.2 Antidiabetic Therapy 
Addition of liothyronine sodium therapy in patients with diabetes mellitus may worsen 
glycemic control and result in increased antidiabetic agent or insulin requirements. 
Carefully monitor glycemic control, especially when Liothyronine Sodium Tablets, USP are 
started, changed, or discontinued [see Warnings and Precautions (5.5)]. 
7.3 Oral Anticoagulants 
Liothyronine sodium 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 liothyronine sodium dose is increased. Closely monitor 
coagulation tests to permit appropriate and timely dosage adjustments. 
7.4 Digitalis Glycosides 
Liothyronine sodium may reduce the therapeutic effects of digitalis glycosides. Serum 
digitalis glycoside levels may be decreased when a hypothyroid patient becomes 
euthyroid, necessitating an increase in the dose of digitalis glycosides. 
7.5 Antidepressant Therapy 
Concurrent use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) 
antidepressants and liothyronine sodium 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 central nervous system 
stimulation. Liothyronine sodium may accelerate the onset of action of tricyclics. 


273 
 
Administration of sertraline in patients stabilized on liothyronine sodium may result in 
increased liothyronine sodium requirements. 
7.6 Ketamine 
Concurrent use of ketamine and liothyronine sodium may produce marked hypertension 
and tachycardia. Closely monitor blood pressure and heart rate in these patients. 
7.7 Sympathomimetics 
Concurrent use of sympathomimetics and liothyronine sodium 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. 
7.8 Tyrosine-Kinase Inhibitors 
Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. 
Closely monitor TSH levels in such patients. 
7.9 Drug-Laboratory Test Interactions 
Consider changes in TBG concentration when interpreting T4 and T3 values. Measure and 
evaluate unbound (free) hormone in this circumstance. Pregnancy, infectious hepatitis, 
estrogens, estrogen-containing oral contraceptives, and acute intermittent porphyria 
increase TBG concentrations. Nephrosis, severe hypoproteinemia, severe liver disease, 
acromegaly, androgens and corticosteroids decrease TBG concentration. Familial hyper- or 
hypo-thyroxine binding globulinemias have been described, with the incidence of TBG 
deficiency approximating 1 in 9000. 
8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
Risk Summary  
Experience with liothyronine use in pregnant women, including data from post-marketing 
studies, have not reported increased rates of major birth defects or miscarriages (see 
Data). There are risks to the mother and fetus associated with untreated hypothyroidism 
in pregnancy. Since TSH levels may increase during pregnancy, TSH should be monitored 
and liothyronine sodium dosage adjusted during pregnancy (see Clinical Considerations). 
There are no animal studies conducted with liothyronine during pregnancy. Liothyronine 
Sodium Tablets, USP should not be discontinued during pregnancy and hypothyroidism 
diagnosed during pregnancy should be promptly treated. 
The estimated background risk of major birth defects and miscarriage for the indicated 
population is unknown. In the U.S. general population, the estimated background risk 


274 
 
of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% 
and 15 to 20%, respectively. 
Clinical Considerations 
Disease-associated maternal and/or embryo/fetal risk 
Maternal hypothyroidism during pregnancy is associated with a higher rate of 
complications, including spontaneous abortion, gestational hypertension, pre-eclampsia, 
stillbirth, and premature delivery. Untreated maternal hypothyroidism may have an 
adverse effect on fetal neurocognitive development. 
Dose adjustments during pregnancy and the postpartum period 
Pregnancy may increase liothyronine sodium requirements. Serum TSH levels should be 
monitored and the liothyronine sodium dosage adjusted during pregnancy. Since 
postpartum TSH levels are similar to preconception values, the liothyronine sodium 
dosage should return to the pre-pregnancy dose immediately after delivery [see Dosage 
and Administration (2.3)] . 
Data 
Human Data 
Liothyronine is approved for use as a replacement therapy for hypothyroidism. Data 
from postmarketing studies have not reported increased rates of fetal 
malformations, miscarriages, or other adverse maternal or fetal outcomes 
associated with liothyronine use in pregnant women. 
8.2 Lactation 
Risk Summary  
Limited published studies report that liothyronine is present in human milk. However, 
there is insufficient information to determine the effects of liothyronine on the 
breastfed infant and no available information on the effects of liothyronine on milk 
production. The developmental and health benefits of breastfeeding should be 
considered along with the mother's clinical need for liothyronine sodium and any 
potential adverse effects on the breastfed infant from liothyronine sodium or from the 
underlying maternal condition. 
8.4 Pediatric Use 
The initial dose of Liothyronine Sodium Tablets, USP varies with age and body weight. 
Dosing adjustments are based on an assessment of the individual patient's clinical and 
laboratory parameters [see Dosage and Administration (2.3, 2.4)]. 


275 
 
In pediatric patients in whom a diagnosis of permanent hypothyroidism has not been 
established, discontinue thyroid hormone for a trial period, but only after the child is at 
least 3 years of age. Obtain serum TSH, T4, and T3 levels at the end of the trial period, and 
use laboratory test results and clinical assessments to guide diagnosis and treatment, if 
warranted [see Dosage and Administration (2.6)]. 
Congenital Hypothyroidism [see Dosage and Administration (2.2, 2.6)]  
Rapid restoration of normal serum T4 concentrations is essential for preventing the 
adverse effects of congenital hypothyroidism on intellectual development as well as on 
overall physical growth and maturation. Therefore, initiate thyroid hormone immediately 
upon diagnosis. Thyroid hormone is generally continued for life in these patients. 
Closely monitor infants during the first 2 weeks of thyroid hormone therapy for 
cardiac overload, arrhythmias, and aspiration from avid suckling. 
Closely monitor patients to avoid undertreatment or overtreatment. Undertreatment may 
have deleterious effects on intellectual development and linear growth. Overtreatment is 
associated with craniosynostosis in infants, may adversely affect the tempo of brain 
maturation, and may accelerate the bone age and result in premature epiphyseal closure 
and compromised adult stature [see Dosage and Administration (2.6) and Adverse 
Reactions (6)]. 
Acquired Hypothyroidism in Pediatric Patients  
Closely monitor patients to avoid undertreatment and overtreatment. 
Undertreatment may result in poor school performance due to impaired 
concentration and slowed mentation and in reduced adult height. Overtreatment 
may accelerate the bone age and result in premature epiphyseal closure and 
compromised adult stature. 
Treated children may manifest a period of catch-up growth, which may be adequate in 
some cases to normalize adult height. In children with severe or prolonged 
hypothyroidism, catch-up growth may not be adequate to normalize adult height [see 
Adverse Reactions (6)]. 
8.5 Geriatric Use 
Because of the increased prevalence of cardiovascular disease among the elderly, initiate 
Liothyronine 
Sodium Tablets, USP at less than the full replacement dose [see Dosage and 
Administration (2.3) and Warnings and Precautions (5.1)] . Atrial arrhythmias can occur in 
elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with 
thyroid hormone overtreatment in the elderly. 


276 
 
10 OVERDOSAGE 
The signs and symptoms of overdosage are those of hyperthyroidism [see Warnings and 
Precautions (5.4) and Adverse Reactions (6)] . In addition, confusion and disorientation may 
occur. 
Cerebral embolism, seizure, shock, coma, and death have been reported. Symptoms may 
not necessarily be evident or may not appear until several days after ingestion. 
Reduce the liothyronine sodium dose or temporarily discontinued if signs or symptoms of 
overdosage occur. Initiate appropriate supportive treatment as dictated by the patient's 
medical status. 
For current information on the management of poisoning or overdosage, contact the 
National Poison Control Center at 1-800-222-1222 or www.poison.org. 
11 DESCRIPTION 
Liothyronine Sodium Tablets, USP contain the active ingredient, liothyronine (L-
triiodothyronine or LT3), a synthetic form of a thyroid hormone liothyronine in sodium 
salt form. It is chemically designated as L-Tyrosine, O-(4-hydroxy-3-iodophenyl)-3,5-
diiodo-, monosodium salt. The molecular formula, molecular weight and structural 
formula of liothyronine sodium are given below. 
 
Liothyronine Sodium Tablets, USP contain liothyronine sodium equivalent to liothyronine in 
5 mcg, 
25 mcg, and 50 mcg. Inactive ingredients consist of calcium sulfate dihydrate, corn 
starch, gelatin, magnesium stearate and mannitol. 
12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
Thyroid hormones exert their physiologic actions through control of DNA transcription 
and protein synthesis. Triiodothyronine (T3) and L-thyroxine (T4) diffuse into the cell 
nucleus and bind to thyroid receptor proteins attached to DNA. This hormone nuclear 
receptor complex activates gene transcription and synthesis of messenger RNA and 
cytoplasmic proteins.  


277 
 
The physiological actions of thyroid hormones are produced predominantly by T3, the 
majority of which (approximately 80%) is derived from T4 by deiodination in peripheral 
tissues. 
12.2 Pharmacodynamics 
The onset of activity of liothyronine sodium occurs within a few hours. Maximum 
pharmacologic response occurs within 2 or 3 days. 
12.3 Pharmacokinetics 
Absorption 
T3 is almost totally absorbed, 95 percent in 4 hours. The hormones contained in the natural 
preparations are absorbed in a manner similar to the synthetic hormones. 
Distribution 
Liothyronine sodium (T3) is not firmly bound to serum protein. The higher affinity of 
levothyroxine 
(T4) for both thyroid-binding globulin and thyroid-binding prealbumin as compared to 
triiodothyronine (T3) partially explains the higher serum levels and longer half-life of the 
former hormone. Both protein-bound hormones exist in reverse equilibrium with minute 
amounts of free hormone, the latter accounting for  the metabolic activity.  
Elimination  
Metabolism 
The major pathway of thyroid hormone metabolism is through sequential deiodination. 
Approximately 80% of circulating T3 is derived from peripheral T4 by monodeiodination. 
The liver is the major site of degradation for both T4 and T3. T3 is further deiodinated to 
diiodothyronine. Thyroid hormones are also metabolized via conjugation with glucuronides 
and sulfates and excreted directly into the bile and gut where they undergo enterohepatic 
recirculation. 
Excretion 
Thyroid hormones are primarily eliminated by the kidneys. A portion of the conjugated 
hormone reaches the colon unchanged and is eliminated in the feces. The biological half-
life is about 2-1/2 days. 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
Animal studies have not been performed to evaluate the carcinogenic potential, 
mutagenic potential or effects on fertility of liothyronine sodium. 


278 
 
16 HOW SUPPLIED/STORAGE AND HANDLING 
Liothyronine Sodium Tablets, USP (white to off-white, round, SC) are supplied as follows: 
 
Strength 
Tablet Markings 
NDC 
5 mcg 
debossed “Σ” on one side and “18” on the other side 
30 count - 42794-018- 
08 
60 count - 42794- 
018-10 
90 count - 42794- 
018-12 
100 count - 42794- 
018-02 
1000 count - 42794- 
018-06 
25 mcg 
debossed “Σ19” on one side and “BISECTED” on 
the other side 
30 count - 42794-019- 
08 
60 count - 42794- 
019-10 
90 count - 42794- 
019-12 
100 count - 42794- 
019-02 
1000 count - 42794- 
019-06 
50 mcg 
debossed “Σ20” on one side and “BISECTED” on 
the other side 
30 count - 42794-020- 
08 
60 count - 42794- 
020-10 
90 count - 42794- 
020-12 
100 count - 42794- 
020-02 
1000 count - 42794- 
020-06 
 
Store between 15°C and 30°C (59°F and 86°F). 


279 
 
17 PATIENT COUNSELING INFORMATION  
 
Dosing and Administration 
 
Instruct patients that Liothyronine Sodium Tablets, USP should only be taken as 
directed by their healthcare provider. 
 Instruct patients to notify their healthcare provider should they become pregnant or 
breastfeeding or are thinking of becoming pregnant, while taking Liothyronine Sodium 
Tablets, USP. 
11.1 Important Information 
 Inform patients that the liothyronine in Liothyronine Sodium Tablets, USP are intended 
to replace a hormone that is normally produced by the thyroid gland. Generally 
replacement therapy is to be taken for life. 
Inform patients that Liothyronine Sodium Tablets, USP should not be used as a primary 
or adjunctive therapy in a weight control program. 
Instruct patients to notify their healthcare provider if they are taking any other 
medications, including prescription and over-the-counter preparations. 
Instruct patients to notify their healthcare provider of any other medical conditions, 
particularly heart disease, diabetes, clotting disorders, and adrenal or pituitary gland 
problems, as the dose of medications used to control these other conditions may need 
to be adjusted while taking Liothyronine Sodium Tablets, USP. If patients are taking 
anticoagulants (blood thinners), their clotting status should be checked frequently. 
 Instruct patients to notify their physician or dentist if they are taking Liothyronine 
Sodium Tablets, USP prior to any surgery. 
11.2 Adverse Reactions 
 Instruct patients to notify their healthcare provider if they experience any of the 
following symptoms: rapid or irregular heartbeat, chest pain, shortness of breath, leg 
cramps, headache, nervousness, irritability, sleeplessness, tremors, change in 
appetite, weight gain or loss, vomiting, diarrhea, excessive sweating, heat 
intolerance, fever, changes in menstrual periods, hives or skin rash, or any other 
unusual medical event [see Adverse Reactions (6)] . 
 Inform patients that partial hair loss may occur rarely during the first few months of 
liothyronine sodium therapy; this is usually temporary [see Adverse Reactions (6)] . 
Manufactured by:  
Sigmapharm Laboratories, LLC  
Bensalem, PA 19020 
OS020-06 REV.0119 


280 
 
12 LIOTHYRONINE SODIUM TABLETS, USP 5 MCG- 90 
TABLETS CONTAINER LABEL 
 
13 LIOTHYRONINE SODIUM TABLETS, USP 5 MCG 
CONTAINER LABEL 
Sigmapharm Laboratories, LLC 
NDC 42794-018-12 
Liothyronine Sodium Tablets, USP 
5 mcg 
90 Tablets 
Rx Only 


281 
 
14 LIOTHYRONINE SODIUM TABLETS, USP 25 MCG- 90 
TABLETS CONTAINER LABEL 
 
15 LIOTHYRONINE SODIUM TABLETS, USP 25 MCG 
CONTAINER LABEL 
Sigmapharm Laboratories, LLC 
NDC 42794-019-12 
Liothyronine Sodium Tablets, USP 
25 mcg 
90 Tablets 
Rx Only 


282 
 
16 LIOTHYRONINE SODIUM TABLETS, USP 50 MCG- 90 
TABLETS CONTAINER LABEL 
 
17 LIOTHYRONINE SODIUM TABLETS, USP 50 MCG 
CONTAINER LABEL 
Sigmapharm Laboratories, LLC 
NDC 42794-020-12 
Liothyronine Sodium Tablets, USP 
50 mcg  
90 Tablets 
Rx Only 
 
 
LIOTHYRONINE SODIUM   
liothyronine sodium tablet 
 
Product Information 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:42794-018 
Route of Administration 
ORAL 
 
 


283 
 
Active Ingredient/Active Moiety 
Ingredient Name 
Basis of Strength 
Strength 
LIOTHYRONINE SODIUM (UNII: GCA9VV7D2N) (LIOTHYRONINE - UNII:06LU7C9H1V) 
LIOTHYRONINE 
5 ug 
 
Inactive Ingredients 
Ingredient Name 
Strength 
CALCIUM SULFATE DIHYDRATE (UNII: 4846Q921YM) 
  
STARCH, CORN (UNII: O8232NY3SJ) 
  
GELATIN (UNII: 2G86QN327L) 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
  
MANNITOL (UNII: 3OWL53L36A) 
  
 
Product Characteristics 
 
Color 
white (white to off-white) 
Score 
no score 
Shape 
ROUND 
Size 
6mm 
Flavor 
Imprint Code 
18 
Contains 
     
Packaging 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:42794-018-02 100 in 1 BOTTLE; Type 0: Not a Combination Product 
12/03/2012 
2 NDC:42794-018-12 90 in 1 BOTTLE; Type 0: Not a Combination Product 
05/01/2018 
3 NDC:42794-018-06 1000 in 1 BOTTLE; Type 0: Not a Combination Produc t 
12/03/2012 
Marketing Information 


284 
 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA200295 
12/03/2012 
LIOTHYRONINE SODIUM   
liothyronine sodium tablet 
Product Information 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:42794-019 
Route of Administration 
ORAL 
Active Ingredient/Active Moiety 
Ingredient Name 
Basis of Strength 
Strength 
LIOTHYRONINE SODIUM (UNII: GCA9VV7D2N) (LIOTHYRONINE - UNII:06LU7C9H1V) 
LIOTHYRONINE 
25 ug 
Inactive Ingredients 
Ingredient Name 
Strength 
CALCIUM SULFATE DIHYDRATE (UNII: 4846Q921YM) 
  
STARCH, CORN (UNII: O8232NY3SJ) 
  
GELATIN (UNII: 2G86QN327L) 
  
MAGNESIUM STEARATE (UNII: 70097M6I30) 
  
MANNITOL (UNII: 3OWL53L36A) 
  
Product Characteristics 
Color 
white (white to off-white) 
Score 
2 pieces 
Shape 
ROUND 
Size 
7mm 
Flavor 
Imprint Code 
19 
Contains 
     


285 
 
Packaging 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:42794-019-02 100 in 1 BOTTLE; Type 0: Not a Combination Product 
12/03/2012 
2 NDC:42794-019-06 1000 in 1 BOTTLE; Type 0: Not a Combination Product 
12/03/2012 
3 NDC:42794-019-12 90 in 1 BOTTLE; Type 0: Not a Combination Product 
05/01/2018 
Marketing Information 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA200295 
12/03/2012 
LIOTHYRONINE SODIUM   
liothyronine sodium tablet 
Product Information 
Product Type 
HUMAN PRESCRIPTION DRUG 
Item Code (Source) 
NDC:42794-020 
Route of Administration 
ORAL 
Active Ingredient/Active Moiety 
Ingredient Name 
Basis of Strength 
Strength 
LIOTHYRONINE SODIUM (UNII: GCA9VV7D2N) (LIOTHYRONINE - UNII:06LU7C9H1V) 
LIOTHYRONINE 
50 ug 
Product Characteristics 
Color 
white (white to off-white) 
Score 
2 pieces 
Shape 
ROUND 
Size 
8mm 


286 
 
Flavor 
Imprint Code 
20 
Contains 
     
Packaging 
# 
Item Code 
Package Description 
Marketing Start Date 
Marketing End Date 
1 NDC:42794-020-02 
100 in 1 BOTTLE; Type 0: Not a Combination Product 
12/03/2012 
2 NDC:42794-020-12 
90 in 1 BOTTLE; Type 0: Not a Combination Product 
05/01/2018 
Marketing Information 
Marketing Category 
Application Number or Monograph Citation 
Marketing Start Date 
Marketing End Date 
ANDA 
ANDA200295 
12/03/2012 
Labeler - SIGMAPHARM LABORATORIES, LLC (556234636) 
 
Registrant - SIGMAPHARM LABORATORIES, LLC (556234636) 
Establishment 
 
Name 
Address 
ID/FEI 
Business Operations 
SIGMAPHARM 
LABORATORIES, LLC 
 
556234636 
manufacture(42794-018, 42794-019, 42794-020) , analysis(42794-018, 
42794019, 42794-020) 
Revised: 8/2019  
SIGMAPHARM LABORATORIES, LLC 
 
 
 
 
 
 
 
 


287 
 
Appendix I 
 
 
 
 
 


288 
 
 


289 
 
 


290 
 
 


291 
 
 


292 
 
 


293 
 
 


294 
 
 

ICF_000.pdf: 
VCU IRB PROTOCOL NUMBER: HM20016169
Version: 6.0 dated 02-23-2023
Page 1 of 23
RESEARCH PARTICIPANT INFORMATION AND CONSENT FORM
STUDY TITLE: Energy Metabolism in Thyroidectomized Patients 
 
VCU INVESTIGATOR:    Angeliki Stamatouli, M.D.
 Phone: (804) 828-3495
SPONSOR: Virginia Commonwealth University
NOTE: In this consent form, “you” always refers to the research participant.
ABOUT THIS CONSENT FORM
You are being invited to participate in a research study because you will undergo total 
thyroidectomy and you will need thyroid hormone therapy. It is important that you carefully 
think about whether being in this study is right for you and your situation.
This consent form is meant to assist you in thinking about whether or not you want to be in this 
study. Please ask the study doctor or the study staff to explain any information in this consent 
document that is not clear to you.  You may take home an unsigned copy of this consent form 
to think about or discuss with family or friends before making your decision.
Your participation is voluntary. You may decide not to participate in this study. If you do 
participate, you may withdraw from the study at any time. Your decision not to take part or to 
withdraw will involve no penalty or loss of benefits to which you are otherwise entitled. 
AN OVERVIEW OF THE STUDY AND KEY INFORMATION
Why is this study being done?
The purpose of this research study is to measure the changes in energy metabolism (how the 
body burns energy), cardiovascular function (heart function), and lipid metabolism (cholesterol 
break down and building) before and after thyroidectomy (surgical removal of thyroid gland) in 
response to two approved therapies for hypothyroidism: levothyroxine (LT4) or 
Liothyronine/levothyroxine (LT3/LT4) combination therapy.
What will happen if I participate?
In this study, Levothyroxine (LT4) and placebo (a look-alike inactive substance, a “sugar pill”) 
will be compared to Liothyronine/ Levothyroxine (LT3/LT4) combination therapy.  
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Version: 6.0 dated 02-23-2023
Page 2 of 23
Levothyroxine LT4 and Liothyronine (LT3) are drugs approved by the U. S. Food and Drug 
Administration (FDA). 
VCU Health COVID-19 Procedures
All subjects will be required follow VCU Health COVID-19 standard of Care screening 
procedures. All subjects will be required to enter the VCU Health Care facility at a location 
specified by the study team.  Please be advised that a mask or face shield will be required 
before entering and during your visit to all VCU Health Care facilities.  If you do not have a 
mask, one will be provided upon entry.  VCU health staff will conduct standard of care COVID-
19 screening as you enter the facility.  If you suspect that you may be positive, have tested 
positive or have been around someone who is or suspected to be positive or tested positive, 
please notify your study team as soon as this information becomes available for guidance.  Do 
not come for your scheduled research appointment.  The study team will provide follow-up 
instructions.
The hospital standard operating procedures require that anyone coming to the hospital for 
inpatient stay must follow all the VCU Health Care facilities COVID-19 protocols. In addition, 
they may need to  have a COVID-19 test done two days (48 hours) to 3 days (72 hours) prior to 
any inpatient admission based upon VCU Health policy. This study involves three-(3) inpatient 
study admission to the hospital: (Baseline, Month 3 and Month 6 study visits).  If required, once 
the study doctor receives the results of the COVID-19 test, he/she will contact you with the 
results and directions for your inpatient scheduled study visits. 
This study requires approximately five study visits. The five-study visits will be a Screening Visit 
(outpatient), one Baseline Visit, (inpatient) one Six Week Visit, (outpatient), one Three Month 
Visit and one Six Month Visit (both inpatient). The COVID-19 test maybe required  to be done 
48 hours (2 days) before each of the three-inpatient visit, Baseline Visit, Three Month and Six 
Month Visit based upon VCU Health policy. If clinically indicated, additional visits can be 
scheduled.
You will be asked to:    
1. Give permission for the researchers to collect information about your medical history 
from your medical records and you five times during the study visits and for 5 years 
after the study visits.
2. Have a Physical exam done 5 times
3.  Up to 24-hour energy expenditure recording in the Whole room indirect calorimeter 
studies 3 times (inpatient overnight stays: Baseline, Three months, and Six months visits)
4. Study drug will be dispensed three times 
5. Have study drug dose adjustments two times
6. Genomic blood draw for DNA one time 
7. Have your blood drawn five times
8. Have an DXA Scan two times
9. Have an Echocardiogram three times
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Version: 6.0 dated 02-23-2023
Page 3 of 23
10. Complete questionnaire three times 
11. Have Accelerometers sensors laced 3 times (inpatient overnight stays: Baseline, Three 
months, and Six months visits), based upon availability
12. Be randomized to take either Levothyroxine LT4 + placebo group or LevothyroxineLT3/ 
Liothyronine LT4 group from baseline through 6 months 
Your participation in this study will last up to 6 months after your surgery. Approximately 30 
total individuals will participate in this study. 
What alternative treatments or procedures are available?
If you decide not to enter the study, you can receive the usual care that you would receive if 
you were not in the study. This include LT4, LT3, or a mixture (at the judgment of your 
physician). 
What are the risks and benefits of participating?
There are both risks and benefits of participating in research studies. We want you to know 
about a few key risks right now. We will give you more information in the “WHAT RISKS AND 
DISCOMFORTS CAN I EXPECT FROM BEING IN THE STUDY?” section.
Risks and Discomforts
Benefits to You and Others
1. Study Drug Risks         
1. There is a risk that the study drug may 
not cause a better outcome as it 
relates to hypothyroid symptoms, 
weight gain, lipid profile, or 
cardiovascular function 
2. There is also a risk that you could 
have side effects from taking study 
drug. Below are some of the most 
common side effects: 
o
Irregular heart beat
o
Chest pain,
o
Anxiety
o
Bone loss
o
Allergic Reaction
2.  Key Procedural Risks 
1. Potential Direct Benefits 
The there is evidence that LT4 and LT3 
combination therapy is effective in treating 
Hypothyroidism.  
This study may help study doctors learn 
things that may help other people in the 
future.
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Version: 6.0 dated 02-23-2023
Page 4 of 23

Venous blood draws may cause pain, 
bleeding, and/or bruising. You may 
faint and could develop an infection 
at the site where blood is drawn. 

Radiation exposure DXA scan 
produces a low dose of X-ray radiation 
comparable to 1/10 of the radiation 
from a chest x-ray. Prolonged 
exposure to radioactivity or to 
multiple tests that use radioactivity 
has been associated with the 
development of anemia or cancer.
Now that you have a general overview of the study, we want to provide the details about what 
your participation involves. Please read, or have someone read to you, the rest of this 
document. If there is anything you do not understand, be sure to ask the study staff.
WHAT WILL HAPPEN IF I PARTICIPATE IN THE STUDY?
Upon entry into any VCU health care facility, all subjects will be required follow VCU Health 
COVID-19 standard of Care screening procedures.
Screening Visit
At your first study visit (called the screening visit), before any procedures are done, if you have 
not done so, we will ask you to read and sign the informed consent after having had all your 
questions and concerns answered to your satisfaction. 
During this visit a trained physician, or nurse will obtain and collect the information required 
for this study. The staff will collect 

Anthropometric information, which include measures of height, weight, temperature, 
and body composition and blood pressure.  

A physical exam will be performed by the study physician 

The study team will collect the following information about your medical history from 
your medical records and you:
o
Your age 
o
Self-reported race/ethnicity 
o
Medical history 
o
Surgical history 
o
Social history 
o
History of medication usage 
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Version: 6.0 dated 02-23-2023
Page 5 of 23

Female subjects will be asked to provide a menstrual history, 
o
Use of contraception, and 
o
Self-reported pregnancy status for the study period. 

In addition, trained staff will collect study blood samples to run the following laboratory 
tests to determine if you can participate in this study. 
o
Thyroid peroxidase antibody (TPO antibodies) 
o
Thyroid Stimulating Hormone (TSH) 
o
Glycated hemoglobin (HbA1c)
This visit will last approximately 30 to 45 minutes.
The results of this visit help the study doctor decide if you are eligible to participate in the 
study.   If you are not eligible, the study doctor will discuss the reason(s) with you.  
If you are eligible to continue, the study coordinator will give (or contact) you with instructions 
for your next study visit called the “Baseline Visit”.  To prepare for next study visit the study 
staff will give you instructions to follow before you come for this visit. 
 
Two days before your next Visit.

You maybe be required to be tested for COVID-19 based upon VCU Health policy.  
Directions for getting the test and the results will be provided to you.  

Please do not do any strenuous exercise and stay on a regular a regular diet for two 
days before you come to be admitted for inpatient Baseline Visit hospital stay.
Baseline Visit
Upon entry into any VCU health care facility, all subjects will be required follow VCU Health 
CIVID-19 standard of Care screening procedures.
At this study visit, you will be admitted to the hospital and stay in the whole room indirect 
calorimeter for up to 24 hours before you will undergo total thyroidectomy. During this stay, a 
24-hour energy expenditure will be recorded in the whole room indirect calorimeter.  
In the morning of the visit, the following procedures will be done before entering the whole 
room indirect calorimeter for up to 24-hour energy expenditure recording. 

A medical history and physical examination, 

An echocardiogram (test that uses sound waves to create pictures of the heart) 

ThyPRO-39 quality of life questionnaire.  If not completed before entering the whole 
room indirect calorimeter, this test can be completed within the first hour while in the 
whole room indirect calorimeter.  
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VCU IRB PROTOCOL NUMBER: HM20016169
Version: 6.0 dated 02-23-2023
Page 6 of 23

You will be fitted with five accelerometers (one on each limb plus chest) to record 
spontaneous movements (done based upon availability)
You will enter the indirect calorimeter room for up to 24-hour energy expenditure recording at 
approximately 11:00 am 
The following procedures will be performed and data recorded while in the whole room 
indirect calorimeter:

You will receive standardized meals at 1:00 pm, (if already entered in the WRIC) and at 
6:00 pm. You will be required to fast (From dinner at 06:00 PM until the end of the 
whole room indirect calorimeter recording at approximately 11:00 AM of the next day), 
about 8-hours overnight fasting and 4 hours fasting during the study.

five accelerometers (one on each limb plus chest) will record your spontaneous 
movements continuously for 24 hours (done based upon availability)

Approximate total energy needs for weight maintenance will be calculated and the 24-
hour energy expenditure will be completed at approximately 11:00 am of the following 
day,
The following procedures will be done after you leave the whole room indirect calorimeter: 

anthropometric measures: height, weight, temperature, blood pressure 

Body composition by DXA scan. 

Venipuncture to collect study blood samples
o
Free Thyroxine (Free T4)
o
Free Triiodothyronine; Total Triiodothyronine (T3)
o
Serum lipids (cholesterol, triglycerides)
o
Serum for storage 
o
Genomic DNA
o
Serum for storage
4
Study drug Randomization 
Randomization will be performed at the end of the baseline visit. You will be randomized (like 
flipping a coin) to the study drugs LT4 plus a placebo (standard of care) or LT3/LT4 combination 
replacement therapy for a six-month period after the surgery. You have one chance in two of 
being assigned to LT4 and placebo, and one chance in two of receiving LT3/LT4 combination 
therapy.  Neither you nor the study doctor will know which study drug you are receiving. This 
information is available to the study doctor if needed in an emergency. This is called blinding, 
and it is done so that a fair evaluation of results may be made. 
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Version: 6.0 dated 02-23-2023
Page 7 of 23
The VCU Investigational Drug Pharmacy will provide color-coded capsules so that you will know 
which tablet to take in the morning “AM” and at night “PM”.
The Thyroid stimulating Hormone (TSH) (a blood test that measures whether you have too 
much, too little or sufficient thyroid hormone) laboratory result is needed for randomization. 
This visit will take approximately up to 30hours.
Your next visit will be approximately six weeks (+7days) following the start of your first dose.
o
Reminder to bring in all unused study medication to your 6 week visit
Six Week Visit (+/-7days) window (it can be conducted virtually at the Principal Investigators’ 
discretion and study participant preference)
Upon entry into any VCU health care facility, all subjects will be required follow VCU Health 
CIVID-19 standard of Care screening procedures.
This is an outpatient visit.  At this visit we the study doctor will:

Review your medical history

Perform a physical exam
The study staff will collect 

Anthropometric measures of height, weight, temperature, blood pressure, body 
composition 

Venipuncture to collect study blood samples 
o
Thyroid Stimulating Hormone (TSH) 
o
Serum for storage
Venous blood samples will be collected for thyroid stimulating hormone (TSH) and 
storage for research. The Thyroid stimulating Hormone (TSH) (a blood test that 
measures whether you have too much, too little or sufficient thyroid hormone) 
laboratory result is needed for dose adjustment and may not be available before you 
leave the clinic. If this happens, the study-unblinded doctor will decide the amount of 
study drug you will need to take once the TSH laboratory results are available; we will 
contact you and mail the medication to you with instructions on how to take your study 
drug. Continue taking the current medication until you receive your new medication.
 This visit will take approximately 30 minutes. 
To prepare for next study visit the study staff will give you instructions to follow before you 
come for this visit.
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Version: 6.0 dated 02-23-2023
Page 8 of 23
Two days before your next Visit.

You may be required to get a tested for COVID-19 based upon hospital policy.  
Directions for getting and the test and results the test will be provided to you.  

Please do not do any strenuous exercise and stay on a regular a regular diet for two days 
before you come to be admitted for inpatient 3-months Visit hospital stay.

Reminder to bring in all unused study medication from your Baseline and 6 week Visit  
to your next visit
Three Month Visit (+/-7days)
You may be required to  have a COVID-19 test done 2 days (48-hours) to 3 days (72- hours) 
before the study visit based upon VCU Health policy. Upon entry into any VCU health care 
facility, all subjects will be required follow VCU Health COVID-19 standard of Care screening 
procedures.
At this study visit, you will be admitted to the hospital and stay in the whole room indirect 
calorimeter for up to 24 hours. During this stay, a 24-hour energy expenditure will be recorded 
in the whole room indirect calorimeter.  
In the morning of the visit, the following procedures will be done before entering the whole 
room indirect calorimeter for 24-hour energy expenditure recording. 

A medical history and physical examination 

An echocardiogram (test that uses sound waves to create pictures of the heart) 

ThyPRO-39 quality of life questionnaire.  If not completed before entering the whole 
room indirect calorimeter, this test can be completed within the first hour while in the 
whole room indirect calorimeter.  

You will be fitted with five accelerometers (one on each limb plus chest) to record 
spontaneous movements done based upon availability
You will enter the indirect calorimeter room for up to 24-hour energy expenditure recording at 
approximately 11:00 am 
The following procedures will be performed and data recorded while in the whole room 
indirect calorimeter:

You will receive standardized meals at 1:00 pm, (if already entered in the WRIC) and at 
6:00 pm.  You will be required to fasting (From dinner at 06:00 PM until the end of the 
whole room indirect calorimeter recording at approximately 11:00 AM of the next day), 
about 8-hours overnight fasting and 4 hours fasting during the study

Five accelerometers (one on each limb plus chest) will record your spontaneous 
movements continuously for 24 hours done based upon availability
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VCU IRB PROTOCOL NUMBER: HM20016169
Version: 6.0 dated 02-23-2023
Page 9 of 23

Approximate total energy needs for weight maintenance will be calculated and the 24-
hour energy expenditure will be completed at approximately 11:00 am of the following 
day
The following procedures will be done after you leave the whole room indirect calorimeter: 

Anthropometric measures: height, weight, temperature, blood pressure 

Venipuncture to collect study blood samples 
o
Thyroid Stimulating Hormone (TSH) 
o
Free Thyroxine (Free T4)
o
Free Triiodothyronine; Total Triiodothyronine (T3)
o
Serum lipids (cholesterol, triglycerides)
o
Serum for storage
This visit will take approximately up to 30 hours.
Dose adjustment of the study drugs, if needed, will be made by the unblinded endocrinologist. 
The study coordinator will give (or contact) you with instructions for your next study visit called 
the “6 months Visit”.  Continue taking the current medication until you receive your new 
medication.
To prepare for next study visit the study staff will give you instructions to follow before you 
come for this visit. 
Two days before your next Visit. (6 Month Visit)

You may be   required to get a tested for COVID-19 based upon VCU Health policy.   
Directions for getting the test and the results will be provided to you.  

 Please do not do any strenuous exercise and stay on a regular a regular diet for two 
days before you come to be admitted.

Reminder to bring in all unused study medication from your 6 week and Month three 
Visit to your next visit
6 Month Visit (+/-7days) window
Upon entry into any VCU health care facility, all subjects will be required follow VCU Health 
COVID-19 standard of Care screening procedures.
At this study visit, you will be admitted to the hospital and stay in the whole room indirect 
calorimeter for up to 24 hours. During this stay, a 24-hour energy expenditure will be recorded 
in the whole room indirect calorimeter.  
In the morning of the visit, the following procedures will be done before entering the whole 
room indirect calorimeter for up to 24-hour energy expenditure recording. 
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VCU IRB PROTOCOL NUMBER: HM20016169
Version: 6.0 dated 02-23-2023
Page 10 of 23

A medical history and physical examination 

An echocardiogram (test that uses sound waves to create pictures of the heart) 

ThyPRO-39 quality of life questionnaire if not completed before entering the whole 
room indirect calorimeter, This test can be completed within the first hour while in the 
whole room indirect calorimeter.  

You will be fitted with five accelerometers (one on each limb plus chest) to record 
spontaneous movements done based upon availability
You will enter the indirect calorimeter room for up to 24-hour energy expenditure recording at 
approximately 11:00 am 
The following procedures will be performed and data recorded while in the whole room 
indirect calorimeter:

You will receive standardized meals at 1:00 pm, (if already entered in the WRIC) and at 
6:00 pm.  You will be required to fasting (From dinner at 06:00 PM until the end of the 
whole room indirect calorimeter recording at approximately 11:00 AM of the next day), 
about 8-hours overnight fasting and 4 hours fasting during the study

Five accelerometers (one on each limb plus chest) will record your spontaneous 
movements continuously for 24 hours maybe done based upon availability

Approximate total energy needs for weight maintenance will be calculated and the 24-
hour energy expenditure will be completed at approximately 11:00 am of the following 
day,
The following procedures will be done after you leave the whole room indirect calorimeter: 

anthropometric measures: height, weight, temperature, blood pressure 

Body composition by DXA scan. 

Venipuncture to collect study blood samples
o
Thyroid Stimulating Hormone (TSH) 
o
Free Thyroxine (Free T4)
o
Free Triiodothyronine; Total Triiodothyronine (T3)
o
Serum lipids (cholesterol, triglycerides)
o
Serum for storage
This visit will take approximately up to 30 hours.
At each visit, you should bring all of your remaining study drug supply to the research clinic.
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Version: 6.0 dated 02-23-2023
Page 11 of 23
The investigators will also collect information from your medical records about other medical 
conditions (for example but not limited to diabetes, hypertension, high cholesterol level), and 
other medications you are taking. Medical record information will be collected during your 
participation in the study and for 5 years after you finish taking the study drug.  At the end of 
the trial, your care will be transferred to your endocrinologist or your primary care provider. 
We will prescribe three-month supply of the levothyroxine or levothyroxine-liothyronine 
combination therapy, based on your preference since both drugs are approved for the 
treatment of hypothyroidism. You or your insurance will be responsible for the cost of this 
prescription since the study is completed.
Study Procedures
Whole Room Indirect Calorimeters also referred to as (Metabolic Chambers)
Whole room indirect calorimeters are rooms that can measure the calories, or energy you burn; 
this measurement is called “energy expenditure”. Each of the three-inpatient visits will include 
a 24-hour recording of energy expenditure in the whole room calorimeter. The whole room 
indirect calorimeter is located in the Clinical Research Service Unit (CRSU) on the eight (8th) 
floor of the North Hospital, on the MCV campus of Virginia Commonwealth University. The 
room calorimeter is a 10’ x 10’ x7’6” room with a window and transparent plexiglass wall. The 
room is fitted with TV, phone, hospital bed, small desk, a toilet behind a privacy screen and a 
vanity. Meals are passed through a port. The room is fitted with Wi-Fi and the door has no lock. 
The enclosed space may cause some minimal discomfort and the ventilation can be noisy, non-
dissimilar to a commercial airplane. Study volunteers can step out the room and withdraw from 
the study at any time, and there is no lock in the calorimeter’s door.
Anthropometric Measurements 
A series of measurements of the muscle, bone, and adipose tissue used to look at the 
composition of the body. The core elements of are height, weight, body mass index (BMI), body 
circumferences (waist, hip, and limbs), and skinfold thickness
Venous Blood Sample Collection. 
We will insert a needle in a vein to collect blood samples at specified times. Study subjects will 
undergo one venipuncture during each of the study visits. Altogether, five blood samples will be 
collected throughout the study for a total of approximately one and a half cup of blood.  All the 
samples collected will be for the research study, except for the measurement of TSH that will 
be used to adjust the therapy.   We will store and analyze your samples for lipids (fats), (TSH) 
Thyroid stimulating Hormone TSH (determinations for dose adjustments), Free (T4) Free 
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Page 12 of 23
Thyroxine and (T3) Triiodothyronine. These blood levels to help evaluate thyroid function and 
diagnose thyroid diseases, including hyperthyroidism and hypothyroidism, TPO (antibodies 
sample will be collected to help determine if the cause of thyroid disease is an autoimmune 
disorder), and other components for hormonal and metabolic factors.  Blood samples will be 
collected at Screening, baseline (pre-surgery), 3-month and 6-month study visits.
Accelerometers 
 The accelerometers are sensing devices that measure a moving object's acceleration and can 
detect frequency and intensity of human movement. They are very similar to “Fitbit” or other 
exercise recording devices.
Genetic Material
This study will use your samples to sequence all or part of your DNA. 
Deoxyribonucleic acid (DNA) is the “blueprint” or “recipe” that gives the body’s cells instructions 
on how to do their jobs. Scientists can use a test called whole genome sequencing to determine 
the order of all or part of the molecules that make up your DNA, like reading all the letters in a 
book. Sequencing is usually done to look for changes in the molecules of DNA that may cause 
health problems. 
Genetic material will be collected during the study to study whether common gene variations 
called “Single Nucleotide Polymorphisms” (SNPs) in gene that regulate the thyroid hormone 
signaling affect the response to the therapy. We do not plan to screen for genetic disease, and 
the information collected are without clinical interest, thus the information will not be provided 
to the volunteers. No genome wide association study will be performed, and the genetic 
material will be disposed of at the end of the study. Study volunteers can opt out the collection 
of genetic material. A genome-wide association study (GWAS) is a type of research to associate 
genetic variations with particular diseases. Genetic variations are common in the population. 
The method involves scanning the genomes from many different people and looking for genetic 
markers that can be used to predict the presence or the risk of developing a disease.
 
Quality of Life assessment
Study participants will be administered ThyPRO-39, a thyroid specific quality of life instrument 
at the baseline (pre-surgery), 3-month and 6-month visit. This questionnaire helps the 
researchers to measure the intensity of the symptoms associated with hypothyroidism, and 
their changes in relation to the therapy. Some individual may experience discomfort by gaining 
introspection in their condition. 
DXA Scan 
DXA stands for dual-energy x-ray absorptiometry (also known as a DEXA scan). It is a simple, 
10-minute test that takes a comprehensive snapshot of your exact breakdown of bone, fat 
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tissue, and muscle mass. The DXA scan is the most accurate and precise body fat test 
available. There are not any special preparations needed, except to stop taking any calcium 
supplements for 24 hours before the test. Study participants are requested to lay still on a table 
while a sensor (similar to an X-ray machine) moves over the body from the head to the feet. 
Wear comfortable clothing. You may have to take off any clothes with metal fasteners, zippers, 
or hooks. Study volunteers will undergo (DXA scan) at the baseline and six-month visits. The 
only potential risk associated with DXA scan is the exposure to radioactivity.
Echocardiogram (echo)
An echocardiogram uses sound waves to produce images of your heart. This common test 
allows your doctor to see your heart beating and pumping blood. Your doctor can use the 
images from an echocardiogram to identify heart disease. For most types of echo, 
you will remove your clothing from the waist up. Women will be given a gown to 
wear during the test. You will lay on your back or left side on an exam table or stretcher. Soft, 
sticky patches called electrodes will be attached to your chest to allow an EKG 
(electrocardiogram) to be done.  The study personnel will spread gel on a device (transducer) 
then presses the transducer firmly against your skin, aiming an ultrasound beam through your 
chest to your heart. The transducer records the sound wave echoes from your heart.  Study 
volunteers will undergo Echo at the baseline three and six-month visits.  The procedure will 
take about 20-30 minutes to complete.
WHAT RISKS AND DISCOMFORTS COULD I EXPERIENCE FROM BEING IN THE STUDY?
Your condition may not get better or may become worse while you are in this study.
Potential Risks  
Research-related risks in this study include those associated with study procedures, namely 
blood drawing, study medications, radiation exposure, and dissemination of Protected Health 
Information (PHI), including genetic data.
No significant risk can be expected from the whole room indirect calorimeter or 
echocardiogram, ™ apparatus. Some individuals may experience anxiety during the stay in the 
indirect calorimeter. Potential additional risks are associated with the collection of genetic 
material and the possible infringement of the study participants’ privacy with dissemination of 
protected health information (PHI). 
Possible Risks associated with Study Drug
Risks associated with excess of LT3 (and to a lesser degree with LT4) include development of 
hyperthyroid symptoms, among them: 

Irregular heart beat

Chest pain
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
anxiety

bone loss
Levothyroxine allergic reaction may include (less common)

skin rash 

hives

flushing
     Possible Risks Associated with Liothyronine allergic reaction may include (less common)

Skin rash

Hives

Itching

Fever

Swelling

Shortness of breath

Wheezing

Runny nose
 An allergic reaction to drugs is possible, but rare. Severe allergic reactions can be life 
threatening.
Only the study participant can take the study drug. It must be kept out of the reach of children 
and persons who may not be able to read or understand the label.
Thyroid hormone medications are considered “narrow index” drugs, and their dose needs to be 
accurate. Many medications can interfere with the thyroid hormone drugs. Please inform the 
study team if during the study your providers make any change in your medication regimen. We 
will provide a card with the information of the study you can show to your other providers. We 
will be happy to talk with your providers if they have any questions related to the study and 
study medications. 
Possible Risk Associated with having Energy expenditure recording: 
The only risk is anxiety or discomfort due to extended period of time fasting (From dinner at 
06:00 PM until the end of the whole room indirect calorimeter recording up to  11:00 AM of the 
next day), about 8-hours overnight fasting and  up to 4 hours fasting during the study) limited 
space available in the whole room indirect calorimeter. Study staff, experienced nurses, and 
hospital physicians will be available to help if you become anxious. If at any time you feel too 
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anxious or uncomfortable, you can simply walk out of the room, as there are no locks on the 
doors.
Possible risks associated with Echo: There is minimal risk associated with this procedure. Some 
individuals are allergic or sensitive to adhesive or latex and may experience skin rash 
(dermatitis) from the electrodes.
Possible risks associated with DXA Scan
There is minimal risk associated with this procedure. DXA scan produces a low dose of X-ray 
radiation comparable to 1/10 of the radiation from a chest x-ray.  
Possible risks with having Blood collection: 
There may be pain at the site where the needle is inserted. Bruising and very rarely infection 
may occur. Some people may experience nausea or faint when the needle is inserted or when 
they see blood. Please inform the study personnel if you have experienced any of these 
reactions before. Bandages used to cover the catheter site may cause a skin rash (dermatitis) in 
some people who are allergic or sensitive to adhesive or latex.
Possible risk with completing ThyPRO-39 quality of life Questionnaire 
 There is minimal risk associated with this procedure. You may experience some emotional  
 discomfort as you assess your perceived quality of life.
Non-Physical Risks
Participation in research might involve some loss of privacy. There is a small risk that someone 
outside the research study could see and misuse information about you.
Questionnaires may contain questions that you may find as sensitive/personal/upsetting in 
nature. You may refuse to answer any question that makes you feel uncomfortable.
This study will ask you questions about personal topics that might be embarrassing to talk 
about and that could affect your family relationships if this information were to become known 
outside of the study. You will also be asked about illegal activities, which could have legal and 
financial consequences if this information were to become known outside of the study.
Genetic Risks:
If known to employers or insurance companies, the results of genetic tests might affect a 
person's ability to obtain a job or health or life insurance. If this information were released, it 
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could be misused. Such misuse could be distressing, and it could cause you or your family 
members to have difficulty obtaining insurance coverage and/or a job. 
A federal law called the Genetic Information Nondiscrimination Act (GINA) makes it illegal for 
health insurance companies, group health plans, and most employers to discriminate against 
you based on your genetic information. However, this legal protection still may not keep 
someone from trying to discriminate against you in this way. It is possible that a genetic test 
might identify a change in the genetic code. This change in the genetic code is called a 
"polymorphism". Polymorphisms are common: some are associated with disease, and some are 
not. Some polymorphisms are being studied for differences in response to thyroid hormone 
therapy, but at this time the data are not clear. We do not expect to find polymorphisms that 
have a known link to diseases. Furthermore, we are not performing whole-genome analysis. 
Therefore, we do not expect that any of the genetic studies' results will cause any potential risk 
if this information were released.
Unknown or Unforeseeable Risks
The researchers will let you know about any significant new findings (such as additional risks or 
discomforts) that might make you change your mind about participating in the study.
Levothyroxine (LT4) and/or Liothyronine/levothyroxine (LT3/LT4) combination therapy may 
involve risks that are currently unknown or unforeseeable.  The use of Liothyronine (LT3) is not 
recommended in pregnancy, and if you are or may become pregnant, your participation in the 
study will be terminated and you will be prescribed Levothyroxine (LT4) and referred to an 
endocrinologist for continuity of care.
Reproductive Risks
As the study procedures might injure an unborn child, pregnant women may not participate. 
Women who might become pregnant should use a medically accepted form of birth control 
such as total abstinence, birth control pills, an IUD, diaphragm, progesterone injections or 
implants, or condoms plus a spermicide. Methods of birth control other than total abstinence 
are not 100% effective, and should a woman become pregnant there is a potential risk of injury 
to an unborn child from exposure to radioactivity via the DXA scan. The use of Liothyronine 
(LT3) is not recommended in pregnancy. For similar reasons, women who are nursing an infant 
may not participate.
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WHAT ARE THE COSTS?
Study drugs will be provided by the sponsor at no cost to you. You will not be charged for any 
study visits, tests, or procedures related to the study. Charges related to the surgery will not be 
covered by the study.
WILL I BE PAID TO PARTICIPATE IN THE STUDY?
You will not be paid for participating in this study. We will provide meals during the 
inpatient visits, meals vouchers for the outpatient visits, and parking vouchers.
 
Please be aware that the investigative team and the University may receive money for the 
conduct of this study.
WHAT HAPPENS IF I AM INJURED OR BECOME SICK BECAUSE I TOOK PART IN THE 
STUDY?
If you are injured by, or become ill, from participating in this study, please contact your study 
doctor immediately. Medical treatment is available at the Virginia Commonwealth University 
Health System (VCU Health System). Your study doctor will arrange for short-term emergency 
care at the VCU Health System or for a referral if it is needed. 
Fees for such treatment may be billed to you or to appropriate third party insurance. Your 
health insurance company may or may not pay for treatment of injuries or illness as a result of 
your participation in this study. To help avoid research-related injury or illness, it is very 
important to follow all study directions.
CAN I STOP BEING IN THE STUDY?
You can stop being in this research study at any time. Leaving the study will not affect your 
medical care, employment status, or academic standing at VCU or VCU Health. Tell the study 
staff if you are thinking about stopping or decide to stop.
If you leave the study before the final regularly scheduled visit, please notify the study doctor 
or the study team. We will help you arrange for your continued care with your physician and 
transition off study medication to standard of care treatment.  We would like you to complete 
the Month 6 Study Visit. Return all unused study medication.  
Your participation in this study may be stopped at any time by the study doctor without your 
consent. The reasons might include:
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●
You become pregnant
●
The study doctor thinks it necessary for your health or safety
●
You are found to not be eligible for the study 
●
The sponsor has stopped the study 
●
You have not followed study instructions
●
Administrative reasons require your withdrawal
●
If you are unable to follow the study instructions 
If you withdraw from the study, data that has already been collected about you will remain part 
of the study database and may not be removed.
HOW WILL INFORMATION ABOUT ME BE PROTECTED?
VCU and the VCU Health System have established secure research databases and computer 
systems to store information and to help with monitoring and oversight of research. Your 
information may be kept in these databases but are only accessible to individuals working on 
this study or authorized individuals who have access for specific research related tasks. 
Identifiable information in these databases are not released outside VCU unless stated in this 
consent or required by law. Although results of this research may be presented at meetings or 
in publications, identifiable personal information about participants will not be disclosed. 
In the future, identifiers might be removed from the information and samples you provide in 
this study, and after that removal, the information/samples could be used for other research 
studies by this study team or another researcher without asking you for additional consent. 
Personal information about you might be shared with or copied by authorized representatives 
from the following organizations for the purposes of managing, monitoring and overseeing this 
study:

The study Sponsor, representatives of the sponsor and other collaborating organizations 

Representatives of VCU and the VCU Health System

Officials of the Department of Health and Human Services or the Federal Food and Drug 
Administration 
It will be noted in your protected electronic health record at VCU Health that you are in this 
study. Information about the study levothyroxine (LT4) and placebo (a look-alike inactive 
substance, a “sugar pill”) will be compared to Liothyronine/levothyroxine (LT3/LT4) 
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combination therapy will be included in the record. This information is protected just as any of 
your other health records are protected. 
In general, we will not give you any individual results from the study. If we find something of 
medical importance to you, we will inform you, although we expect that this will be a very rare 
occurrence. You will be informed of the results of the screening tests, phenotype studies, 
including body composition, energy expenditure, and echocardiogram.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the 
Website will include a summary of the results. You can search this Web site at any time.
If you tell us that you may hurt yourself or someone else, the law says that we must let people in 
authority know.
There are no plans to share any money or profits with you if the use of your sample(s) results in 
inventions or discoveries that have commercial value. 
Certificate of Confidentiality
To help us protect your privacy, we will apply for a Certificate of Confidentiality from the 
National Institutes of Health. If this certificate is obtained, it will offer the protections described 
here. A Certificate of Confidentiality helps the researchers keep your information private. For 
example, researchers can refuse to give out your information in a court case.  Researchers may 
have to give your information if the study is audited, or if the information is required by the 
Food and Drug Administration (FDA).
The researchers may share information about you or your participation in the research project 
without your consent if you intend to make voluntary disclosure about things such as child 
abuse, elder abuse or intent to hurt self or others, or other voluntary disclosures
The researchers cannot prevent you or others, for example a member of your family, from 
sharing information about you or your involvement in this research. If you give an insurer, 
employer, or other person permission to receive research information, then the researchers 
may not use the Certificate to withhold that information.
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HOW WILL MY HEALTH INFORMATION BE USED AND SHARED DURING THIS STUDY?
As part of this research study, we will ask you to share identifiable health information with us 
and/or permit us to access existing information from your healthcare records. New health 
information may also be created from study-related tests, procedures, visits, and/or 
questionnaires. This type of information is considered “Protected Health Information” that is 
protected by federal law. 
What type of health information will be used or shared with others during this research?
The following types of information may be used for the conduct of this research:
 Complete health record
 Diagnosis & treatment codes
 Discharge summary
 History and physical exam
 Consultation reports
 Progress notes
 Laboratory test results
 X-ray reports
 X-ray films / images
 Photographs, videotapes
 Complete billing record
 Itemized bill
 Information about drug or alcohol abuse
 Information about Hepatitis B or C tests
 Information about mental health 
 Information about sexually transmitted diseases
 Other physical or mental health information (specify):      
Who will use or share protected health information about me?
VCU and VCU Health are required by law to protect your identifiable health information. By 
consenting to this study, you authorize VCU/VCU Health to use and/or share your health 
information for this research. The health information listed above may be used by and/or 
shared with the following people and groups to conduct, monitor, and oversee the research:
●
Principal Investigator and Research Staff 
●
Study Sponsor 
●
Health Care Providers at VCU Health 
●
Data Coordinators 
●
Institutional Review Boards 
●
Research Collaborators 
●
Government/Health Agencies 
●
Data Safety Monitoring Boards 
●
Others as Required by Law
Once your health information has been disclosed to anyone outside of this study, the 
information may no longer be protected under this authorization.
When will this authorization (permission) to use my protected health information expire? 
This authorization will expire when the research study is closed, or there is no need to review, 
analyze and consider the data generated by the research project, whichever is later.
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Statement of Privacy Rights
You may change your mind and revoke (take back) the right to use your protected health 
information at any time. However, even if you revoke this authorization, the researchers may 
still use or disclose health information they have already collected about you for this study. If 
you revoke this Authorization, you may no longer be allowed to participate in the research 
study. To revoke this Authorization, you must write to the Principal Investigator at 
Angeliki Stamatouli, M.D.
Virginia Commonwealth University
Sanger Hall 7th Floor, Room 7-0108
1101 East Marshall Street
Richmond, VA 23298
OPTIONAL STORAGE FOR FUTURE RESEARCH STUDIES 
To advance science, it is helpful for researchers to share information. They do this by putting 
data or samples into one or more scientific databases (called registries or repositories), where it 
is stored along with information from other studies. Researchers can then study the 
information in other ways and combine information from many studies to learn even more 
about health and disease.
As part of this study, we would like to keep the information and/or samples that you provide, 
along with your name, phone, address and email a registry to be available for other research 
studies in the future. Your information and samples would be stored at VCU by Angeliki 
Stamatouli, M.D.  for three years after the analysis of the study is complete and could be used 
for other research studies about hypothyroidism. Your data/samples will be protected, but 
there is always a possibility that information could be accessed by individuals without 
authorization. 
In the future, if you decide that you do not want to be part of this registry, you can request that 
your information/samples be removed and destroyed by contacting Angeliki Stamatouli, M.D.. 
However, information that has already been shared with other researchers will continue to be 
used.
Angeliki Stamatouli, M.D.
 
Virginia Commonwealth University
Sanger Hall 7th Floor, Room 7-0108
1101 East Marshall Street
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Richmond, VA 23298
Phone: (804) 828-3495
 
Fax: (804) 828-8389   
Permission to Store Data and Samples for Future Research Studies
Please circle your answer: I agree that my data and samples may be stored and used for future 
research as described above.
   YES
NO
WHOM SHOULD I CONTACT IF I HAVE QUESTIONS ABOUT THE STUDY?
The investigator and study staff named below are the best person(s) to contact if you have any 
questions, complaints, or concerns about your participation in this research:  Contact the 
principle Investigator or the research Coordinator:
Principal Investigator
                                        Research Coordinator:
Angeliki Stamatouli, M.D.
Joyce R Ruddley BSN, RN, CCRP
Virginia Commonwealth University
Virginia Commonwealth University
Sanger Hall 7th Floor, Room 7-0108
Sanger Hall 8th Floor, Room 8-062
1101 East Marshall Street
1101 East Marshall Street
Richmond, VA 23298
Richmond, VA 23298
Phone: (804) 828-3495
Phone: (804) 828-9684; 
Fax: (804) 828-8389   
Fax: (804) 828-5717
What if you have l questions about your rights as a research participant?
If you have general questions about your rights as a participant in this or any other research, or 
if you wish to discuss problems, concerns or questions, to obtain information, or to offer input 
about research, you may contact:
Virginia Commonwealth University Office of Research
800 East Leigh Street, Suite 3000, Box 980568, Richmond, VA 23298
(804) 827-2157; https://research.vcu.edu/human_research/volunteers.htm 
Do not sign this consent form unless you have had a chance to ask questions and have received 
satisfactory answers to all of your questions. 
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STATEMENT OF CONSENT 
I have been provided with an opportunity to read this consent form carefully. All of the 
questions that I wish to raise concerning this study have been answered. By signing this consent 
form, I have not waived any of the legal rights or benefits to which I otherwise would be 
entitled. My signature indicates that I freely consent to participate in this research study. I will 
receive a copy of the consent form for my records.
Signature Block for Enrolling Adult Participants
________________________________________________
Adult Participant Name (Printed)
________________________________________________
________________
Adult Participant’s Signature 
Date
________________________________________________
Witness Name (Printed) if available
________________________________________________
________________
Signature of Witness
Date
________________________________________________
Name of Person Conducting Consent Discussion (Printed)
________________________________________________
________________
Signature of Person Conducting Consent Discussion
Date
________________________________________________
________________
Principal Investigator Signature (if different from above) 
Date 
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