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.

TIROSINT (NDA-021924)

(LEVOTHYROXINE SODIUM)

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

Download Data

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12/08/2017 (SUPPL-13)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

TIROSINT is contraindicated in patients with uncorrected adrenal insufficiency.

5 Warnings and Precautions

Newly added information below:

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

Overtreatment 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 TIROSINT therapy in this population at lower doses than those recommended in younger individuals or in patients without cardiac disease.

Monitor for cardiac arrhythmias during surgical procedures in patients with coronary artery disease receiving suppressive TIROSINT therapy. Monitor patients receiving concomitant TIROSINT and sympathomimetic agents for signs and symptoms of coronary insufficiency. If cardiac symptoms develop or worsen, reduce the TIROSINT dose or withhold it 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 precipitate an acute adrenal crisis in patient with adrenal insufficiency. Treat patients with adrenal insufficiency with replacement glucocorticoids prior to initiating treatment with TIROSINT.

5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism

Additions and/or revisions underlined:

TIROSINT has a narrow therapeutic index. Over- or under-treatment with TIROSINT 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 TIROSINT carefully and monitor response to titration to avoid these effects. Monitor for the presence of drug or food interactions when using TIROSINT and adjust the dose as necessary.

5.5 Worsening of Diabetic Control

(Newly added)

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 thyroid hormone therapy.

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

Additions and/or revisions underlined:

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 TIROSINT that achieves the desired clinical and biochemical response to mitigate against this risk.

6 Adverse Reactions

Additions and/or revisions underlined:

Adverse reactions associated with TIROSINT 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

7 Drug Interactions

7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics

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

Tirosint replaces levothyroxine in all drug naming instances

Addition of Proton Pump Inhibitors to Other Drugs category with the added effect:

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 Tirosint absorption. Monitor patients appropriately.

Table 3: Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)

Table has undergone numerous revisions; please refer to label for complete information.

Table 4: Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)

Table has undergone numerous revisions; please refer to label for complete information.

Table 5: Drugs That May Decrease Conversion of T4 to T3

Addition of the following effect for Amiodarone:

Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decrease or normal free-T3) in clinically euthyroid patients.

7.2 Antidiabetic Therapy

Addition of TIROSINT therapy in patients with diabetes mellitus may worsen glycemic control and result in increased antidiabetic agent or insulin requirements. Careful monitor glycemic control, especially when thyroid therapy is started, changed, or discontinued.

7.4 Digitalis Glycosides

TIROSINT 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.

7.6 Ketamine

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

7.7 Sympathomimetics

Concurrent use of sympathomimetics and TIROSINT may increase the effects of sympathomimetics or thyroid hormone …

8 Use in Specific Populations

PLLR conversion; additions and/or revisions underlined:

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. There are risks to the mother and fetus associated with untreated hypothyroidism in pregnancy. Since thyroid-stimulating hormone (TSH) levels may increase during pregnancy, TSH should be monitored and TIROSINT dosage adjusted during pregnancy. There are no animal studies conducted with levothyroxine during pregnancy. TIROSINT 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 TIROSINT requirements. Serum TSH level should be monitored and the TIROSINT dosage adjusted during pregnancy. Since postpartum TSH levels are similar to preconception values, the TIROSINT dosage should return to the pre- pregnancy dose immediately after delivery.

Thyroid 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

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

8.4 Pediatric Use

Additions and/or revisions underlined:

TIROSINT is indicated for use in pediatric patients 6 years and older. The initial dose of levothyroxine TIROSINT varies with age and body weight …

In children in whom a diagnosis of permanent hypothyroidism has not been established, discontinue TIROSINT administration for a trial period. Obtain serum T4 and TSH levels should be obtained at the end of the trial period, and use laboratory test results and clinical assessments to guide diagnosis and treatment, if warranted.

Congenital Hypothyroidism

… Therefore, initiate levothyroxine therapy should be initiated immediately upon diagnosis and. Levothyroxine is generally continued for life in these patients.

Closely monitor children during the first two weeks of TIROSINT therapy for cardiac overload and arrhythmias.

Closely monitor patients to avoid undertreatment and overtreatment. Undertreatment may have deleterious effects on intellectual development and linear growth. Overtreatment may adversely affect the tempo of brain maturation and accelerate the bone age with resultant premature closure of the epiphyses and compromised adult stature.

Acquired Hypothyroidism in Pediatric Patients

Closely monitor patients to avoid undertreatment and overtreatment …

8.5 Geriatric Use

Additions and/or revisions underlined

Because of the increased prevalence of cardiovascular disease among the elderly, initiate TIROSINT therapy 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)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient and/or the caregiver to read the FDA-approved patient labeling (Patient Information Sheet).

Dosing and Administration

Instruct patients to take TIROSINT only as directed by their healthcare provider.
Instruct patients to take TIROSINT 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 TIROSINT within 4 hours of these agents.
Instruct patients that TIROSINT capsules should be swallowed whole and never be cut, crushed, or chewed.
To assist with identifying the name and strength of each TIROSINT capsule, instruct patients not to remove capsules from the blisters in advance, particularly if they are taking multiple strengths.
Instruct patients to notify their healthcare provider should they become pregnant or are thinking of becoming pregnant while taking TIROSINT.

Important Information

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 TIROSINT. 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 TIROSINT prior to any surgery.

PATIENT INFORMATION

Newly added section; please refer to label for complete information.

04/25/2017 (SUPPL-12)

5 Warnings and Precautions

Addition of the following:

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

5.2 Myxedema Coma

Newly created subsection from information similarly states elsewhere in label; revised as below:

Addition of the following:

5.3 Acute Adrenal Crisis in Patients with Concomitant Adrenal Insufficiency

Additions and/or revisions underlined:

5.4 Prevention of Hyperthyroidism or Incomplete Treatment of Hypothyroidism

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

6 Adverse Reactions

Additions and/or revisions underlined:

Adverse reactions associated with TIROSINT 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

7 Drug Interactions

Additions and/or revisions underlined:

7.1 Drugs Known to Affect Thyroid Hormone Pharmacokinetics

Many drugs can exert effects thyroid hormone pharmacokinetics (e.g., absorption, synthesis, secretion, catabolism, protein binding, and target tissue response) and may alter the therapeutic response to TIROSINT (see Tables 2 to 5 below).

7.2 Antidiabetic Therapy

Addition of TIROSINT 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.

7.6 Ketamine

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

7.9 Drug-Food Interactions

Consumption of certain foods may affect TIROSINT absorption thereby necessitating adjustments in dosing. Soybean flour (infant formula), cottonseed meal, walnuts, and dietary fiber may bind and decrease the absorption of TIROSINT from the GI tract. Grapefruit juice may delay the absorption of levothyroxine and reduce its bioavailability.

8 Use in Specific Populations

8.1 Pregnancy

PLLR Conversion, revised as below:

Risk Summary

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

Dose Adjustments during Pregnancy and the Postpartum Period

Data

Human Data

8.2 Lactation

PLLR conversion; revised as below:

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

8.4 Pediatric Use

Additions and/or revisions underlined:

TIROSINT is indicated for use in pediatric patients 6 years and older. The initial dose of TIROSINT varies with age and body weight. Dosing adjustments are based on an assessment of the individual patient's clinical and laboratory parameters.

In children in whom a diagnosis of permanent hypothyroidism has not been established, discontinue TIROSINT administration for a trial period. Obtain serum T4 and TSH levels at the end of the trial period, and use laboratory test results and clinical assessments to guide diagnosis and treatment, if warranted.

Congenital Hypothyroidism.

… Therefore, initiate levothyroxine therapy immediately upon diagnosis. Levothyroxine is generally continued for life in these patients. Closely monitor children during the first two weeks of TIROSINT therapy for cardiac overload and arrhythmias. Closely monitor patients to avoid undertreatment and overtreatment. Undertreatment may have deleterious effects on intellectual development and linear growth. Overtreatment may adversely affect the tempo of brain maturation and accelerate the bone age with resultant premature closure of the epiphyses and compromised adult stature.

Acquired Hypothyroidism in Pediatric Patients

Closely monitor patients to avoid undertreatment and overtreatment. Undertreatment may result in poor school performance.

8.5 Geriatric Use

Additions and/or revisions underlined:

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient and/or the caregiver to read the FDA-approved patient labeling (Patient Information Sheet). Dosing and Administration

Instruct patients that TIROSINT capsules should be swallowed whole and never be crushed or cut.
Instruct patients to notify their healthcare provider should they become pregnant or are thinking of becoming pregnant while taking TIROSINT.
Important Information

… as the dose of medications used to control these other conditions may need to be adjusted while taking TIROSINT. 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 TIROSINT prior to any surgery.

PATIENT INFORMATION

Newly added subsection; please refer to label.