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.

ISOVUE-128 (NDA-018735)

(IOPAMIDOL)

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

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10/10/2025 (SUPPL-75)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Risks Associated with Intrathecal Administration

Additions and/or revisions underlined:

Intrathecal administration of ISOVUE, even if inadvertent, can cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis,hyperthermia, and brain edema. ISOVUE is for intra-arterial, intravenous, or oral use only [see Dosage and Administration (2.2, 2.3, 2.4, 2.5)].

5.2 Hypersensitivity Reactions

Additions and/or revisions underlined:

ISOVUE can cause life-threatening or fatal hypersensitivity reactions including anaphylaxis. Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock [see Adverse Reactions (6.2)]. Most severe reactions develop shortly after the start of administration (e.g., within 1 to 3 minutes), but delayed reactions can also occur.

…

5.3 Acute Kidney Injury

Acute kidney injury, including renal failure, may occur after intavascular administration of ISOVUE. Risk factors include: pre-existing renal insufficiency, dehydration, diabetes mellitus, congestive heart failure, advanced vascular disease, elderly age, concomitant use of nephrotoxic or diuretic medications, multiple myeloma or other paraproteinemias, and repetitive or large doses of ISOVUE.

…

5.4 Cardiovascular Adverse Reactions

Additions and/or revisions underlined:

Intravascular administration of ISOVUE increases the circulatory osmotic load and may induce acute or delayed hemodynamic disturbances in patients with congestive heart failure, severely impaired renal function, combined renal…

…

5.6 Extravasation and Injection Site Reactions

Additions and/or revisions underlined:

Extravasation can occur with intravascular ISOVUE administration, particularly in patients with severe arterial or venous disease.

…

5.7 Thyroid Storm in Patients with Hyperthyroidism

Additions and/or revisions underlined:

Thyroid storm has occurred after the intravascular use of iodinated contrast agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of ISOVUE.

…

5.9 Hypertensive Crisis in Patients with Pheochromocytoma

Additions and/or revisions underlined

Hypertensive crisis in patients with pheochromocytoma has occurred with iodinated contrast agents. Closely monitor patients when administering ISOVUE intravascularly if pheochromocytoma or catecholamine-secreting…

5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease

Additions and/or revisions underlined:

ISOVUE administered intravascularly can promote sickling in individuals who are homozygous for sickle cell disease. Hydrate patients prior to and following ISOVUE administration and use only if the necessary imaging information cannot be obtained with alternative imaging modalities.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Adverse Reactions from Intra-arterial Use in Pediatric Patients

In a clinical trial with 76 pediatric patients undergoing angiocardiography, two adverse reactions (2.6%) were reported: worsening cyanosis and worsening peripheral perfusion.

Adverse Reactions from Oral Use in Adult and Pediatric Patients

There were no new adverse reactions from oral use of ISOVUE in adult and pediatric patients [see Clinical Studies (14)].

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post approval use of ISOVUE or other iopamidol-containing products by intra-arterial, intravenous, or oral administration. Because the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.

…

Eye disorders: lacrimation increased, conjunctivitis, eye pruritus, transient blindness, visual disturbance, photophobia, eyelid edema

Gastrointestinal disorders: nausea, vomiting, diarrhea, retching, esophageal pain, abdominal pain, salivary hypersecretion, salivary gland enlargement, oral paresthesia, lip swelling

…

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP), erythema multiforme and drug reaction with eosinophilia and systemic symptoms (DRESS), skin necrosis, urticaria, face edema

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of ISOVUE have been established in pediatric patients for intra-arterial administration for angiocardiography and for intravenous administration for excretory urography and contrast computed tomography (head and body).

The safety and effectiveness of ISOVUE have been established in pediatric patients for oral administration for CT of the abdomen and pelvis to delineate the gastrointestinal tract. Use of ISOVUE for this indication is supported by evidence from an adequate and well-controlled clinical study in adults (n=152) and pediatric patients 3 to 16 years of age (n=66) who underwent CT of the abdomen and pelvis with oral administration of ISOVUE and from additional safety data from post-approval use of enteral iopamidol in adult and pediatric patients [see Adverse Reactions (6.2)] and Clinical Studies (14)].

12/06/2024 (SUPPL-73)

Approved Drug Label (PDF)

5 Warnings and Precautions

The following subsections created to comply with Physician Labeling Rule (PLR), please refer to label for complete information.

5.1 Risks Associated with Intrathecal Administration

5.2 Hypersensitivity Reactions

5.3 Acute Kidney Injury

5.4 Cardiovascular Adverse Reactions

5.5 Thromboembolic Events

5.6 Extravasation and Injection Site Reactions

5.7 Thyroid Storm in Patients with Hyperthyroidism

5.8 Thyroid Dysfunction in Pediatric Patients 0 Years to 3 Years of Age

5.9 Hypertensive Crisis in Patients with Pheochromocytoma

5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease

5.11 Severe Cutaneous Adverse Reactions

5.12 Interference with Laboratory Tests

7 Drug Interactions

7.1 Drug-Drug Interactions

Additions and/or revisions underlined:

Metformin

In patients with renal impairment, metformin can cause lactic acidosis. Iodinated contrast agents appear to increase the risk of metformin-induced lactic acidosis, possibly as a result of worsening renal function.

Stop metformin at the time of, or prior to, ISOVUE administration in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast agents. Re-evaluate eGFR 48 hours after the imaging procedure and reinstitute metformin use only after renal function is stable.

Radioactive Iodine

Administration of ISOVUE may interfere with thyroid uptake of radioactive iodine (I-131 and I-123) and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post ISOVUE.

7.2 Drug-Laboratory Test Interactions

Additions and/or revisions underlined:

Protein-Bound Iodine Test

Iodinated contrast agents, including ISOVUE, will temporarily increase protein-bound iodine in blood. Avoid protein-bound iodine test for at least 16 days following administration of ISOVUE. However, thyroid function tests that do not depend on iodine estimations, e.g., triiodothyronine (T3) resin uptake and total or free thyroxine (T4) assays, are not affected.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion:

Risk Summary

Available data from published literature and postmarketing cases from decades of use with iopamidol during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Iopamidol crosses the placenta and reaches fetal tissues in small amounts (see Data). In animal reproduction studies, no adverse developmental outcomes were observed with intravenous administration of iopamidol to pregnant rats and rabbits during organogenesis at doses up to 2.7 and 1.4 times, respectively, the maximum recommended human dose (see Data).

The 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.

Data

Human Data

Literature reports show that intravenously administered iopamidol crosses the placenta and is visualized in the digestive tract of exposed infants after birth.

Animal Data

Iopamidol did not affect fetal development and did not induce teratogenic changes in the offspring in either rats or rabbits at the following dose levels tested: 600 mg, 1,500 mg, or 4,000 mg iodine/kg in rats, administered intravenously once a day during days 6 through 15 of pregnancy; 300 mg, 800 mg, or 2,000 mg iodine/kg in rabbits, administered intravenously once a day during days 6 through 18 of pregnancy.

8.2 Lactation

PLLR conversion:

Risk Summary

There are no data on the presence of iopamidol in human milk, the effects on the breastfed infant, or the effects on milk production. Iodinated contrast agents are present unchanged in human milk in very low amounts, with poor absorption from the gastrointestinal tract of a breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ISOVUE and any potential adverse effects on the breastfed infant from ISOVUE or from the underlying maternal condition.

Clinical Considerations

Interruption of breastfeeding after exposure to iodinated contrast agents is not necessary because the potential exposure of the breastfed infant to iodine is small. However, a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 10 hours (approximately 5 half- lives) after ISOVUE administration in order to minimize drug exposure to a breastfed infant.

8.4 Pediatric Use

Additions and/or revisions underlined:

…

The safety and effectiveness of ISOVUE for cerebral, peripheral, and selective visceral arteriography, aortography, coronary arteriography, cardiac ventriculography, and peripheral venography have not been established in pediatric patients.

8.5 Geriatric Use

New subsection added to comply with Physician labeling Rule (PLR):

Iopamidol is excreted by the kidney, and the risk of adverse reactions to ISOVUE may be greater in patients with renal impairment. Because patients 65 years of age and older are more likely to have renal impairment, care should be taken in dose selection, and it may be useful to monitor renal function [see Warnings and Precautions (5.3) and Use in Specific Populations [8.6]).

8.6 Renal Impairment

New subsection added to comply with Physician Labeling Rule (PLR):

The clearance of iopamidol decreases with increasing degree of renal impairment and results in delayed opacification of the urinary system. In addition, preexisting renal impairment increases the risk for acute kidney injury [see Warnings and Precautions (5.3)]. Iopamidol can be removed by dialysis.

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

PATIENT COUNSELING INFORMATION

Section added to comply with Physician Labeling Rule (PLR):

Hypersensitivity Reactions

Advise the patient concerning the risk of hypersensitivity reactions that can occur both during and after ISOVUE administration. Advise the patient to report any signs or symptoms of hypersensitivity reactions during the procedure and to seek immediate medical attention for any signs or symptoms experienced after discharge [see Warnings and Precautions (5.2)].

Advise patients to inform their physician if they develop a rash after receiving ISOVUE [see Warnings and Precautions (5.11)].

Acute Kidney Injury

Advise the patient concerning appropriate hydration to decrease the risk of contrast induced kidney injury

[see Warnings and Precautions (5.3)].

Extravasation

If extravasation occurs during injection, advise patients to seek medical care for progression of symptoms

[see Warnings and Precautions (5.6)].

Thyroid Dysfunction

Advise parents/caregivers about the risk of developing thyroid dysfunction after ISOVUE administration. Advise parents/caregivers about when to seek medical care for their child to monitor for thyroid function [see Warnings and Precautions (5.8)].

Lactation

Advise a lactating woman that interruption of breastfeeding is not necessary, however, to minimize exposure to a breastfed infant, a lactating woman may consider pumping and discarding breast milk for 10 hours after ISOVUE administration [see Use in Specific Populations (8.2)].

Other

Physician Labeling Rule (PLR) conversion.

04/25/2023 (SUPPL-70)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age:

Additions and/or revisions underlined:

Thyroid dysfunction characterized by hypothyroidism or transient thyroid suppression has been reported after both single exposure and multiple exposures to iodinated contrast media in pediatric patients 0 to 3 years of age.

Younger age, very low birth weight, prematurity, underlying medical conditions affecting thyroid function, admission to neonatal or pediatric intensive care units, and congenital cardiac conditions are associated with an increased risk of hypothyroidism after ICM exposure. Pediatric patients with congenital cardiac conditions may be at greatest risk given that they often require high doses of contrast during invasive cardiac procedures.

An underactive thyroid during early life may be harmful for cognitive and neurological development and may require thyroid hormone replacement therapy. After exposure to ICM, individualize thyroid function monitoring based on underlying risk factors, especially in term and preterm neonates.

PRECAUTIONS

Pediatric Use

Additions and/or revisions underlined:

…

After exposure to iodinated contrast media, individualize thyroid function monitoring in pediatric patients 0 to 3 years of age based on underlying risk factors, especially in term and preterm neonates (see WARNINGS and ADVERSE REACTIONS).

02/18/2022 (SUPPL-67)

Approved Drug Label (PDF)

5 Warnings and Precautions

PRECAUTIONS

Information for Patients

Newly added information:

6. Advise parents/caregivers about the risk of developing thyroid dysfunction after ISOVUE administration. Advise parents/caregivers about when to seek medical care for their child to monitor for thyroid function (see WARNINGS).

Pediatric Use

Newly added information:

Thyroid function tests indicative of thyroid dysfunction, characterized by hypothyroidism or transient thyroid suppression have been uncommonly reported following iodinated contrast media administration in pediatric patients, including term and preterm neonates; some patients were treated for hypothyroidism. Monitor pediatric patients 0 to 3 years of age closely, particularly those with one or more potential risk factors, for thyroid dysfunction (see WARNINGS and ADVERSE REACTIONS).

WARNINGS

Newly added information:

Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age: Thyroid dysfunction characterized by hypothyroidism or transient thyroid suppression has been reported after both single exposure and multiple exposures to iodinated contrast media. Among patients 0 to 3 years of age exposed to iodinated contrast media, thyroid dysfunction has been reported in 1% to 15% depending on the age of the patient and the dose of the iodinated contrast agent.

Younger age, very low birth weight, prematurity, and the presence of other conditions, such as, admission to neonatal or pediatric intensive care units, and cardiac conditions are associated with an increased risk. Pediatric patients with cardiac conditions may be at the greatest risk given that they often require high doses of contrast during invasive cardiac procedures, such as catheterization and computed tomography (CT).

Pediatric patients 0 to 3 years of age warrant closer monitoring because an underactive thyroid during early life may be harmful for motor, hearing, and cognitive development and may require transient T4 replacement therapy. Evaluate thyroid function in all pediatric patients 0 to 3 years of age within 3 weeks following exposure to iodinated contrast media, especially in term and preterm neonates. If thyroid dysfunction is detected, treat and monitor thyroid function as clinically needed.

6 Adverse Reactions

Additions and/or revisions underlined:

Endocrine: hyperthyroidism, hypothyroidism

04/05/2017 (SUPPL-57)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

(additions underlined)

General

…

Severe Cutaneous Adverse Reactions: Severe cutaneous adverse reactions (SCAR) may develop from 1 hour to several weeks after intravascular contrast agent administration. These reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS). Reaction severity may increase and time to onset may decrease with repeat administration of contrast agent; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering Isovue to patients with a history of a severe cutaneous adverse reaction to Isovue.

6 Adverse Reactions

(additions underlined)

General Adverse Reactions To Contrast Media

…

Tissue Disorders: Skin necrosis; Reactions range from mild (e.g. rash, erythema, pruritus, urticaria and skin discoloration) to severe: [e.g. Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS)].

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

Information for Patients

(addition underlined)

1. Inform your physician if you are pregnant.

2. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease, or known thyroid disorder.

3. Inform your physician if you are allergic to any drugs, food, or if you had any reactions to previous injections of substances used for x-ray procedures.

4. Inform your physician about any other medications you are currently taking, including nonprescription drugs, before you have this procedure.

5. Advise patients to inform their physician if they develop a rash after receiving Isovue.