Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

ULTRAVIST 370 (NDA-020220)

(IOPROMIDE)

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

Download Data

Expand all

05/25/2023 (SUPPL-54)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Risks Associated with Intrathecal Use

(Additions and/or revisions underlined)

Intrathecal administration, even if inadvertent, can cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. ULTRAVIST is for intra-arterial or intravenous use only [see Dosage and Administration (2.2, 2.3, 2.4)]. ULTRAVIST is not approved for intrathecal use.

5.2 Hypersensitivity Reactions

(Additions and/or revisions underlined)

ULTRAVIST 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 injection (e.g., within 1 to 3 minutes), but delayed reactions can also occur.

There is increased risk of hypersensitivity reactions in patients with a history of previous reaction to a contrast agent and known allergic disorders (that is, bronchial asthma, allergic rhinitis, and food allergies), or other hypersensitivities.

Premedication with antihistamines or corticosteroids does not prevent serious life-threatening reactions but may reduce both their incidence and severity.

Obtain a history of allergy, hypersensitivity, or hypersensitivity reactions to iodinated contrast agents and have emergency resuscitation equipment and trained personnel available prior to ULTRAVIST administration. Monitor all patients for hypersensitivity reactions.

5.3 Acute Kidney Injury

(Additions and/or revisions underlined)

Acute kidney injury, including renal failure, may occur after administration of ULTRAVIST. 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 paraproteinemia, and repetitive and/or large doses of ULTRAVIST.

Use the lowest necessary dose of ULTRAVIST in patients with renal impairment. Hydrate patients prior to and following ULTRAVIST administration. Do not use laxatives, diuretics, or preparatory dehydration prior to ULTRAVIST administration.

5.4 Cardiovascular Adverse Reactions

(Additions and/or revisions underlined)

ULTRAVIST 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 and hepatic disease, or combined renal and cardiac disease, particularly when repetitive and/or large doses are administered. Fatal cardiovascular reactions have occurred mostly within 10 minutes of ULTRAVIST injection; the main feature was cardiac arrest with cardiovascular disease as the main underlying factor. Hypotensive collapse and shock have occurred. Cardiac decompensation, serious arrhythmias, and myocardial ischemia or infarction can occur during coronary arteriography and ventriculography.

The administration of ULTRAVIST may cause pulmonary edema in patients with heart failure. Based upon published reports, deaths from the administration of iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Use the lowest necessary dose of ULTRAVIST in patients with congestive heart failure and always have emergency resuscitation equipment and trained personnel available. Monitor all patients for severe cardiovascular reactions.

5.5 Thromboembolic Events

(Additions and/or revisions underlined)

Serious, in some cases fatal, thromboembolic events causing myocardial infarction and stroke can occur during angiography procedures. During these procedures, increased thrombosis and activation of the complement system can occur. Risk of thromboembolic events can be influenced by: length of procedure, catheter and syringe material, underlying disease state, and concomitant medications. To decrease thromboembolic events, use meticulous angiographic techniques and minimize the length of the procedure. Avoid blood remaining in contact with syringes containing iodinated contrast agents, which increases the risk of clotting. Avoid angiography in patients with homocystinuria because of the risk of inducing thrombosis and embolism.

5.6 Extravasation and Injection Site Reactions

(Additions and/or revisions underlined)

Extravasation can occur with ULTRAVIST, particularly in patients with severe arterial or venous disease. Inflammation, blistering, skin necrosis, and compartment syndrome have been reported following extravasation. In addition, injection site reactions such as pain and swelling at the injection site can also occur [see Adverse Reactions (6.1)]. Ensure intravascular placement of catheters prior to injection. Monitor patients for extravasation and advise patients to seek medical care for progression of symptoms.

5.8 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 (ICM) 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 the 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.

The safety and effectiveness of ULTRAVIST in pediatric patients younger than 2 years of age have not been established, and ULTRAVIST is not approved for use in pediatric patients younger than 2 years of age [see Use in Specific Populations (8.4)]

5.9 Hypertensive Crisis in Patients with Pheochromocytoma

(Newly added subsection)

Hypertensive crisis in patients with pheochromocytoma has occurred with iodinated contrast agents. Closely monitor patients when administering ULTRAVIST if pheochromocytoma or catecholamine-secreting paragangliomas are suspected. Inject the minimum amount of ULTRAVIST necessary and have measures for treatment of a hypertensive crisis readily available.

5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease

(Newly added subsection)

Iodinated contrast agents may promote sickling in individuals who are homozygous for sickle cell disease. Hydrate patients prior to and following ULTRAVIST administration and use only if the necessary imaging information cannot be obtained with alternative imaging modalities.

5.12 Interference with Laboratory Tests

(Newly added subsection)

ULTRAVIST can interfere with protein-bound iodine test [see Drug Interactions (7.2)].

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are described elsewhere in the labeling:

·     Risks Associated with Intrathecal Use [see Warnings and Precautions (5.1)]

·     Hypersensitivity Reactions [see Warnings and Precautions (5.2)]

·     Acute Kidney Injury [see Warnings and Precautions (5.3[FF1] )]

·      Cardiovascular Adverse Reactions [see Warnings and Precautions (5.4)]

·     Thromboembolic Events [see Warnings and Precautions (5.5)]

·     Extravasation and Injection Site Reactions [see Warnings and Precautions (5.6)]

·     Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age [see Warnings and Precautions (5.8)]

·     Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.11)]

 

6.1 Clinical Trials Experience

(Extensive changes; please refer to label for complete information)

7 Drug Interactions

7.1 Drug-Drug Interactions

Metformin

(Additions and/or revisions underlined)

In patients with renal impairment, biguanides 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, ULTRAVIST 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 only after renal function is stable.

Radioactive Iodine

ULTRAVIST 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 ULTRAVIST.

7.2 Drug-Laboratory Test Interactions

(Additions and/or revisions underlined)

Protein-Bound Iodine Test

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

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and efficacy of ULTRAVIST have been established in pediatric patients aged 2 years and older for radiographic evaluation of cardiac chambers and related arteries, excretory urography, and contrast computed tomography of head and body. Use of ULTRAVIST in these age groups for these indications is supported by evidence from adequate and well-controlled studies in adults and additional safety data in pediatric patients aged 2 years and older, including data from published studies [see Adverse Reactions (6.1, 6.2) and Clinical Studies (14.1, 14.2)].

Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent include those with asthma, sensitivity to medication and/or allergens, cyanotic and acyanotic heart disease, congestive heart failure, or serum creatinine greater than 1.5 mg/dL.

Thyroid function tests indicative of thyroid dysfunction, characterized by hypothyroidism or transient thyroid suppression have been reported following iodinated contrast media administration in pediatric patients, including term and preterm neonates; Some patients were treated for hypothyroidism. 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 Precautions (5.8) and Adverse Reactions (6.2)].

Safety and effectiveness of ULTRAVIST have not been established in pediatric patients younger than 2 years for radiographic evaluation of cardiac chambers and related arteries, excretory urography, and contrast computed tomography of head and body.

Safety and effectiveness of ULTRAVIST for cerebral arteriography, peripheral arteriography, coronary arteriography and left ventriculography, visceral angiography, aortography, and contrast mammography have not been established in pediatric patients.

8.5 Geriatric Use

(Additions and/or revisions underlined)

In a clinical study of ULTRAVIST for CT, 96/434 (22.1%) of patients were 65 and over. No overall differences in safety were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients. Iopromide is known to be substantially excreted by the kidney, and the risk of adverse reactions to iopromide 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.

8.6 Renal Impairment

(Additions and/or revisions underlined)

The clearance of iopromide decreases with increasing degree of renal impairment and results in delayed opacification of the urinary system [see Clinical Pharmacology (12.3)]. In addition, preexisting renal impairment increases the risk for acute kidney injury [see Warnings and Precautions (5.3)]. Iopromide can be removed by dialysis.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Hypersensitivity Reactions

Advise the patient concerning the risk of hypersensitivity reactions that can occur both during and after ULTRAVIST 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 ULTRAVIST [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 ULTRAVIST 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 lactating women that interruption of breast feeding is not necessary, however, to avoid any exposure a lactating woman may consider pumping and discarding breast milk for 12 to 24 hours after ULTRAVIST administration [see Use in Specific Populations (8.2)].

04/25/2023 (SUPPL-56)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 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 (ICM) 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 the 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.

…

8 Use in Specific Populations

8.4 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 Precautions (5.6) and Adverse Reactions (6.2)],

…

02/18/2022 (SUPPL-52)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.6 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.

The safety and effectiveness of ULTRAVIST in pediatric patients younger than 2 years of age have not been established, and ULTRAVIST is not approved for use in pediatric patients younger than 2 years of age [see Use in Specific Populations (8.4)]

8 Use in Specific Populations

8.4 Pediatric Use

Newly added information:

Thyroid function tests indicative of thyroid dysfunction, characterized by hypothyroidism or transient thyroid suppression have been 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 Precautions (5.6) and Adverse Reactions (6.2)].

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

PATIENT COUNSELING INFORMATION

Newly added information:

Thyroid Dysfunction – Advise parents/caregivers about the risk of developing thyroid dysfunction after ULTRAVIST administration. Advise parents/caregivers about when to seek medical care for their child to monitor for thyroid function [see Warnings and Precautions (5.6)].

08/01/2019 (SUPPL-47)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

There are no data on ULTRAVIST Injection use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Iopromide crosses the placenta and reaches fetal tissues in small amounts (see Data). In animal reproduction studies, intravenous administration of iopromide to pregnant rats and rabbits during organogenesis at doses up to 0.35 and 0.7 times, respectively, the maximum recommended human dose based on body surface area resulted in no relevant adverse developmental effects (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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

Limited case reports demonstrate that intravenously administered iodinated contrast agents, including iopromide, cross the placenta and are visualized in the digestive tract of exposed infants after birth.

Animal Data

Reproduction studies performed with intravenous iopromide in rats (day 6 to 15 of gestation) and rabbits (day 6 to 18 of gestation) at dose levels of 0, 0.37, 1.11 and 3.7 g iodine per kg corresponding to doses up to 0.35 times (rats) and 0.7 times (rabbits) the maximum human recommended dose based on body surface area. Iopromide was not teratogenic at any dose level in rats and rabbits and embryolethality was observed in rabbits that received 3.7 g iodine per kg, but this was considered to have been secondary to maternal toxicity.

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of iopromide in human milk, the effects on the breastfed infant, or the effects on milk production. Iodinated contrast agents are poorly excreted into human milk and are poorly absorbed by 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 ULTRAVIST Injection and any potential adverse effects on the breastfed infant from ULTRAVIST Injection or from the underlying maternal condition (see Clinical Considerations).

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 12 to 24 hours (approximately 5 elimination half-lives) after ULTRAVIST Injection administration in order to minimize drug exposure to a breast fed infant.

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

PATIENT COUNSELING INFORMATION

(subsection revised, additions underlined)

…

• Advise lactating women that interruption of breast feeding is not necessary, however, a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 12 to 24 hours (approximately 5 elimination half-lives) after ULTRAVIST Injection administration to minimize exposure to the breastfed infant

04/02/2018 (SUPPL-45)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

 …

Skin and subcutaneous tissue disorders: 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)].

 ...

7 Drug Interactions

7.1 Drug-Drug Interactions

(Additions and/or revisions are underlined)

 …

Do not mix other drugs with ULTRAVIST Injection except saline.

 

04/05/2017 (SUPPL-42)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Severe Cutaneous Adverse Reactions

(new subsection added)

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 ULTRAVIST to patients with a history of a severe cutaneous adverse reaction to ULTRAVIST.

6 Adverse Reactions

6.2 Postmarketing Experience

(addition underlined)

The following adverse reactions have been identified during post approval use of ULTRAVIST Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions reported in foreign postmarketing surveillance and other trials with the use of ULTRAVIST Injection include:

...

Skin and subcutaneous tissue disorders: 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)

(addition underlined)

Instruct patients receiving ULTRAVIST Injection to inform their physician or healthcare provider of the following:

…

•   Advise patients to inform their physician if they develop a rash after receiving ULTRAVIST