Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

SYNTHROID (NDA-021402)

(LEVOTHYROXINE SODIUM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/20/2024 (SUPPL-38)

Approved Drug Label (PDF)

7 Drug Interactions

7.10 Drug-Laboratory Test Interactions

Additions and/or revisions underlined:

Thyroxine-binding Globulin (TBG)

…

Biotin

Biotin supplementation is known to interfere with thyroid hormone immunoassays that are based on a biotin and streptavidin interaction, which may result in erroneous thyroid hormone test results. Stop biotin and biotin-containing supplements for at least 2 days prior to thyroid testing.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Important Information

…

Instruct patients to discontinue biotin or any biotin-containing supplements for at least 2 days before thyroid function testing is conducted.
…

08/30/2022 (SUPPL-36)

Approved Drug Label (PDF)

5 Warnings and Precautions

Renumbered subsection title; additions and/or revisions underlined:

5.1 Serious Risks Related to Overtreatment or Undertreatment with SYNTHROID

SYNTHROID has a narrow therapeutic index. Overtreatment or undertreatment with SYNTHROID may have negative effects on growth and development, cardiovascular function, bone metabolism, reproductive function, cognitive function, gastrointestinal function, and glucose and lipid metabolism in adult or pediatric patients.

In pediatric patients with congenital and acquired hypothyroidism, undertreatment may adversely affect cognitive development and linear growth, and overtreatment is associated with craniosynostosis and acceleration of bone age [see Use in Specific Populations (8.4)].

Titrate the dose of SYNTHROID carefully and monitor response to titration to avoid these effects [see Dosage and Administration (2.4)]. Consider the potential for food or drug interactions and adjust the administration or dosage of SYNTHROID as needed [see Dosage and Administration (2.1), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].

6 Adverse Reactions

6.1 Clinical Trials Experiences

Additions and/or revisions underlined:

Adverse Reactions in Pediatric Patients (‘pediatric patients’ replaces ‘children’ throughout subsection)

Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in pediatric patients receiving levothyroxine therapy. Overtreatment may result in craniosynostosis in infants who have not undergone complete closure of the fontanelles, and in premature closure of the epiphyses in pediatric patients still experiencing growth with resultant compromised adult height.

7 Drug Interactions

7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics

Additions and/or revisions underlined (including table # changes):

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 SYNTHROID (Tables 5 to 8).

Table 5. Drugs That May Decrease T4 Absorption (Hypothyroidism)

Table 6. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)

Table 7. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)

Table 8. Drugs That May Decrease Conversion of T4 to T3

8 Use in Specific Populations

Additions and/or revisions underlined:

8.1 Pregnancy

Risk Summary

The clinical experience, including data from postmarketing studies, in pregnant women treated with oral levothyroxine to maintain euthyroid state have not reported increased rates of major birth defects, miscarriages, or other adverse maternal or fetal outcomes. 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 SYNTHROID dosage adjusted during pregnancy (see Clinical Considerations). Animal reproductive studies have not been conducted with levothyroxine sodium. SYNTHROID 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. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

8.2 Lactation

Published studies report that levothyroxine is present in human milk following the administration of oral levothyroxine. No adverse effects on the breastfed infant have been reported and there is no information on the effects of levothyroxine on milk production. Adequate levothyroxine treatment during lactation may normalize milk production in hypothyroid lactating mothers with low milk supply. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SYNTHROID and any potential adverse effects on the breastfed infant from SYNTHROID or from the underlying maternal condition.

8.4 Pediatric Use

SYNTHROID is indicated in patients from birth to less than 17 years of age:

As a replacement therapy in primary (thyroidal), secondary (pituitary), and tertiary (hypothalamic) congenital or acquired hypothyroidism.
As an adjunct to surgery and radioiodine therapy in the management of thyrotropin- dependent well-differentiated thyroid cancer.

Rapid restoration of normal serum T4 concentrations is essential for preventing the adverse effects of congenital hypothyroidism on cognitive development as well as on overall physical growth and maturation. Therefore, initiate SYNTHROID therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients [see Warnings and Precautions (5.1)].

Closely monitor infants during the first 2 weeks of SYNTHROID therapy for cardiac overload and arrhythmias.

8.5 Geriatric Use

Because of the increased prevalence of cardiovascular disease among the elderly, initiate SYNTHROID at less than the full replacement dose [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)]. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly.

07/15/2020 (SUPPL-34)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics

(Additions and/or revisions underlined)

Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism)

Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.

Drug or Drug Class

Phosphate Binders

(e.g., calcium carbonate, ferrous sulfate, sevelamer, lanthanum)

Effect

Phosphate binders may bind to levothyroxine. Administer SYNTHROID at least 4 hours apart from these agents.

02/23/2017 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Cardiac Adverse Reactions in the Elderly and in Patients with Underlying Cardiovascular Disease

(Additions and/or revisions are underlined; revised subsection title)

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…Monitor patients receiving concomitant SYNTHROID and sympathomimetic agents for signs and symptoms of coronary insufficiency.

5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency

(Additions and/or revisions are underlined; newly added subsection title)

…Initiation of thyroid hormone therapy prior to initiating glucocorticoid therapy may precipitate an acute adrenal crisis in patients with adrenal insufficiency…

5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism

(Additions and/or revisions are underlined; newly added subsection title)

…Monitor for the presence of drug or food interactions when using SYNTHROID and adjust the dose as necessary.

5.5 Worsening of Diabetic Control

(Additions and/or revisions are underlined; newly added subsection title)

Addition of levothyroxine therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements…

5.6 Decreased Bone Mineral Density Associated with Thyroid Hormone Over-Replacement

(Additions and/or revisions are underlined; revised subsection title)

Increased bone resorption and decreased bone mineral density may occur as a result of levothyroxine over-replacement, particularly in post-menopausal women…Administer the minimum dose of SYNTHROID that achieves the desired clinical and biochemical response to mitigate this risk.

6 Adverse Reactions

(Additions and/or revisions are underlined)

Adverse reactions associated with SYNTHROID therapy are primarily those of hyperthyroidism due to therapeutic overdosage. They include the following:

Musculoskeletal: tremors, muscle weakness, muscle spasm
Dermatologic: hair loss, flushing, rash

Adverse Reactions in Children

Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children…

Hypersensitivity Reactions

Hypersensitivity reactions to inactive ingredients have occurred…

7 Drug Interactions

7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics

(Additions and/or revisions are underlined; newly added subsection title)

Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism) (Table has been revised; please refer to label)

Table 3. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism) (Table has been added; please refer to label)

Table 4. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism) (Table has been added; please refer to label)

Table 5. Drugs That May Decrease Conversion of T4 to T3(Table has been added; please refer to label)

7.2 Antidiabetic Therapy

(Additions and/or revisions are underlined; newly added subsection title)

Addition of SYNTHROID therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements…

7.5 Antidepressant Therapy

(Newly added subsection title)

7.6 Ketamine

(Additions and/or revisions are underlined; newly added subsection title)

Concurrent use of ketamine and SYNTHROID may produce marked hypertension and tachycardia. Closely monitor blood pressure and heart rate in these patients.

7.7 Sympathomimetics

(Newly added subsection title)

7.9 Drug-Food Interactions

(Additions and/or revisions are underlined)

…Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

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. 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 SYNTHROID dosage adjusted during pregnancy. There are no animal studies conducted with levothyroxine during pregnancy. SYNTHROID 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

…Untreated maternal hypothyroidism may have an adverse effect on fetal neurocognitive development.

Dose Adjustments During Pregnancy and the Postpartum Period

Pregnancy may increase SYNTHROID requirements. Serum TSH levels should be monitored and the SYNTHROID dosage adjusted during pregnancy…

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

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

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 SYNTHROID and any potential adverse effects on the breastfed infant from SYNTHROID or from the underlying maternal condition.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

…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.

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Because of the increased prevalence of cardiovascular disease among the elderly, initiate SYNTHROID at less than the full replacement dose. Atrial arrhythmias can occur in elderly patients. Atrial fibrillation is the most common of the arrhythmias observed with levothyroxine overtreatment in the elderly.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Inform the patient of the following information to aid in the safe and effective use of SYNTHROID:

Dosing and Administration

Instruct patients to take SYNTHROID only as directed by their healthcare provider.
Instruct patients to take SYNTHROID 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 SYNTHROID 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 SYNTHROID.

Important Information

Inform patients that it may take several weeks before they notice an improvement in symptoms.
Inform patients that the levothyroxine in SYNTHROID 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 SYNTHROID 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 SYNTHROID. 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 SYNTHROID 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…
Inform patients that partial hair loss may occur rarely during the first few months of SYNTHROID therapy, but this is usually temporary.

Other

(Physician Labeling Rule (PLR) Conversion; please refer to label)

02/23/2017 (SUPPL-28)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics

(Additions and/or revisions are underlined; newly added subsection title)

Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism) (Table has been revised to include Proton Pump Inhibitors (PPIs); please refer to label)

7.8 Tyrosine-Kinase Inhibitors

(Newly added subsection)

Concurrent use of tyrosine-kinase inhibitors such as imatinib may cause hypothyroidism. Closely monitor TSH levels in such patients.