Drug Safety-related Labeling Changes (SrLC)

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OPTIRAY 240 (NDA-019710)

(IOVERSOL)

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

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04/25/2023 (SUPPL-67)

Approved Drug Label (PDF)

5 Warnings and Precautions

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.

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 (5.8) and Adverse Reactions (6.2)].

05/04/2022 (SUPPL-64)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

 WARNING: RISKS WITH INADVERTENT INTRATHECAL ADMINISTRATION

 FOR INTRA-ARTERIAL AND INTRAVENOUS USE ONLY

Inadvertent intrathecal administration may cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. (5.1)

02/18/2022 (SUPPL-65)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.8 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

Newly added to the bulleted line listing:

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

6.2 Postmarketing Experience

Additions and/or revisions underlined:

… Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure.

Endocrine disorders: Hyperthyroidism, hypothyroidism

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

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 Precautions (5.8) 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 OPTIRAY administration. Advise parents/caregivers about when to seek medical care for their child to monitor for thyroid function. [see Warnings and Precautions (5.8)].

01/23/2020 (SUPPL-58)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Risk Summary

Postmarketing data with Optiray use in pregnant women are insufficient to determine if there is a risk of drug-associated adverse developmental outcomes. Ioversol crosses the placenta and reaches fetal tissues in small amounts [see Data]. In animal reproduction studies, no adverse developmental effects were observed following daily intravenous administrations of ioversol to pregnant rats (from Gestation Day 7 to 17) and rabbits (Gestation Day 6 to 18) at doses 0.35 and 0.71 times, respectively, the maximum recommended human dose.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

04/26/2017 (SUPPL-54)

Approved Drug Label (PDF)

Boxed Warning

PLR conversion, addition of the following:

WARNING: NOT FOR INTRATHECAL USE

Inadvertent intrathecal administration may cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema.

4 Contraindications

PLR conversion: addition of the following:

Symptomatic hyperthyroidism.

5 Warnings and Precautions

PLR conversion, revised as below:

5.1 Risks Associated with Inadvertent Intrathecal Administration

Optiray is indicated for intravascular use only.   Inadvertent intrathecal administration can cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema.

5.2 Hypersensitivity Reactions

Optiray can cause life-threatening or fatal hypersensitivity reactions including anaphylaxis and anaphylactic shock.   Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock. Most severe reactions develop shortly after the start of the injection (e.g. within 1 to 3 minutes), but delayed reactions may occur. There is an increased risk in patients with a history of a previous reaction to contrast agent, and known allergies (i.e., bronchial asthma, drug, or food allergies), and other hypersensitivities. Premedication with antihistamines or corticosteroids to avoid or minimize possible allergic reactions does not prevent serious life-threatening reactions, but may reduce both their incidence and severity.

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

5.3 Contrast Induced Acute Kidney Injury

Acute kidney injury, including renal failure, may occur after Optiray administration. Risk factors include:   pre-existing renal impairment, dehydration, diabetes mellitus, congestive heart failure, advanced vascular disease, elderly age, concomitant use of nephrotoxic or diuretic medications, multiple myeloma / paraproteinaceous diseases, repetitive and/or large doses of an iodinated contrast agent.

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

5.4 Cardiovascular Adverse Reactions

Optiray 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, combined renal and cardiac disease, particularly when repetitive or large doses are administered.

Life-threatening or fatal cardiovascular reactions have occurred with the use of Optiray, including cardiac arrest, hypotensive collapse, and shock. Most deaths occur within 10 minutes of injection; with cardiovascular disease as the main underlying factor. Cardiac decompensation, serious arrhythmias, and myocardial ischemia or infarction can occur during coronary arteriography and ventriculography.

Based upon literature 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 Optiray 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

Angiocardiography

 fatal, thromboembolic events causing myocardial infarction and stroke can occur during angiographic procedures with Optiray. During these procedures, increased thrombosis and activation of the complement system occurs. Risk factors for thromboembolic events include: length of procedure, catheter and syringe material, underlying disease state, and concomitant medications.

To minimize thromboembolic events use meticulous angiographic technique. Avoid blood remaining in contact with syringes containing Optiray, which increases the risk of clotting.   Avoid angiocardiography in patients with homocystinuria because of the risk of inducing thrombosis and embolism.

5.6 Extravasation and Injection Site Reactions

Extravasation can occur with Optiray administration, particularly in patients with severe arterial or venous disease and can be associated with pain, hemorrhage and necrosis. Ensure intravascular placement of catheters prior to injection. Monitor patients for extravasation and advise patients to seek medical care for progression of symptoms.

5.7 Thyroid Storm in Patients with Hyperthyroidism

Optiray is contraindicated in patients with symptomatic hyperthyroidism. Thyroid storm has occurred following the intravascular use of iodinated radiopaque agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of Optiray.

5.8 Hypertensive Crisis in Patients with Pheochromocytoma

 Hypertensive crisis has occurred after the use of iodinated radiopaque contrast agents in patient with pheochromocytoma. Closely monitor patients when administering Optiray if pheochromocytoma or catecholamine-secreting paraganglioma is suspected. Inject the minimum amount of Optiray necessary and have measures for treatment of hypertensive crisis readily available.

5.9 Sickle Cell Crisis in Patients with Sickle Cell Disease

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

5.10 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 a contrast agent; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering Optiray to patients with a history of a severe cutaneous adverse reaction to Optiray.

6 Adverse Reactions

PLR conversion; revised as below:

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Risks Associated with Inadvertent Intrathecal Administration

• Hypersensitivity Reactions

• Contrast Induced Acute Kidney Injury

• Cardiovascular Adverse Reactions

• Thromboembolic Events

• Severe Cutaneous Adverse Reactions

6.1 Clinical Studies Experience

Adult Patients

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following listing shows adverse reactions based upon clinical trials with Optiray (ioversol) in 4,187 patients. Adverse reactions are listed by organ system according to clinical importance. More severe reactions are listed before others in a system regardless of incidence. The most common reaction is nausea, occurring at a rate of 1 percent.

Cardiac disorders

Cardiac arrest, myocardial infarction, arrhythmia, atrioventricular block complete, atrioventricular block, nodal rhythm, bradycardia, angina pectoris, palpitations

Ear and labyrinth disorders

Vertigo, tinnitus

Eye disorders

Vision blurred, periorbital edema, conjunctivitis

Gastrointestinal disorders

Nausea, vomiting, abdominal pain, dysphagia, dry mouth

General disorders and administration site conditions

Chest pain, pain, injection site pain, injection site hematoma, extravasation, pyrexia, swelling, asthenia, malaise, fatigue, chills

Infections and infestations

Rhinitis

Injury, poisoning, and procedural complications

Heart injury, vascular pseudoaneurysm

Investigations

Electrocardiogram ST segment depression, blood pressure decreased

Metabolism and nutrition disorders

Acidosis

Musculoskeletal and connective tissue disorders

Muscular weakness, muscle spasms, back pain

Nervous system disorders

Cerebral infarction, aphasia, tremor, dizziness, presyncope, headache, paresthesia, dysgeusia

Psychiatric disorders

Hallucination, visual hallucination, disorientation, anxiety

Renal and urinary disorders

Urinary retention, renal pain, polyuria

Respiratory, thoracic, and mediastinal disorders

Laryngeal edema, hypoxia, pulmonary edema, dyspnea, hyperventilation, cough, sneezing, nasal congestion

Skin and subcutaneous tissue disorders

Urticaria, rash, pruritus, swelling face, hyperhidrosis, erythema

Vascular disorders

Hypertension, hypotension, arterial spasm, vasospasm, vasodilation, flushing

Pediatric Patients

In clinical trials involving 311 patients for pediatric angiocardiography, contrast enhanced computed tomographic imaging of the head and body, and intravenous excretory urography; 6% of patients reported adverse reactions, with the most common adverse reactions being nausea and fever. Adverse reactions reported were similar in quality and frequency to the adverse events reported by adults.

6.2 Postmarketing Experience

The following adverse drug reactions have been reported during post-approval use of Optiray. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency.

Cardiac disorders: coronary artery spasm, cyanosis, arrhythmia (ventricular fibrillation, tachycardia, extrasystole), ECG abnormal.

Endocrine disorders: thyroid function tests indicative of hypothyroidism or transient thyroid suppression have been uncommonly reported following iodinated contrast media administration to adult and pediatric patients, including infants, some patients were treated for hypothyroidism.

Eye disorders: temporary blindness, conjunctivitis (including eye irritation, ocular hyperemia, watery eyes).

Gastrointestinal disorders: tongue edema, salivary hypersecretion.

General disorders and administration site conditions: injection site reactions including pain, hemorrhage, and necrosis especially after extravasation. face edema, feeling hot.

Immune system disorders: hypersensitivity reactions including fatal anaphylactic shock.

Nervous system disorders: seizure, loss of consciousness, somnolence, hypoesthesia, dyskinesia, amnesia.

Respiratory disorders: respiratory arrest, asthma, bronchospasm, laryngeal spasm and obstruction, throat irritation, dysphonia.

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).

Vascular Disorders: phlebitis, thrombosis.

7 Drug Interactions

PLR conversion; revised as below:

7.1 Drug-Drug Interactions

• 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, Optiray 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

  Administration of iodinated contrast agents may interfere with thyroid uptake of radioactive iodine (I-131) and decrease therapeutic efficacy in patients with carcinoma of the thyroid. The decrease in efficacy lasts for 6-8 weeks.

• Oral Cholecystographic Contrast Agents

  Renal toxicity has been reported in patients with liver impairment who were given oral cholecystographic agents followed by intravascular contrast agents. Administration of Optiray should be postponed in patients who have recently received a cholecystographic contrast agent.

7.2 Drug/Laboratory Test Interactions

Protein-Bound Iodine, Radioactive Iodine Determinations

The results of protein bound iodine and radioactive iodine uptake studies, which depend on iodine estimation, will not accurately reflect thyroid function for up to 16 days following administration of iodinated contrast agent. However, thyroid function tests that do not depend on iodine estimations, e.g., T3 resin uptake and total or free thyroxine (T4) assays are not affected.

8 Use in Specific Populations

PLR and PLLR conversion; revised as below:

8.1 Pregnancy

Risk Summary

Postmarketing data with Optiray use in pregnant women are insufficient to determine if there is a risk of drug-associated adverse developmental outcomes. Ioversol crosses the placenta and reaches fetal tissues in small amounts.  In animal reproduction studies, no adverse developmental effects were observed following intravenous administration of ioversol to pregnant rats and rabbits at doses 0.35 and 0.71 times, respectively, the maximum recommended human dose.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Human Data

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

Animal Data

Developmental toxicity studies were conducted with ioversol given intravenously at doses of 0, 0.2,

0.8 and 3.2 g iodine/kg/day from Gestation Day 7 to 17 and 6 to 18, in rats and rabbits, respectively. No adverse effects on embryo-fetal development were observed in either species at the maximum dose tested (3.2 g iodine/kg/day). Maternal toxicity was observed in rabbits at 0.8 and 3.2 g iodine/kg/day.

8.2 Lactation

Risk Summary

There is no information about the presence of ioversol in human or animal milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, iodinated contrast agents are excreted unchanged in human milk in very low amounts with poor absorption from the gastrointestinal tract of the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Optiray and any potential adverse effects on the breastfed infant from Optiray 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 8 hours (approximately 5 elimination half-lives) after Optiray administration in order to minimize drug exposure to a breast fed infant.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have been established for the use of Optiray 350 and Optiray 320 in angiocardiography; and for Optiray 320 in computed tomographic imaging of the head and body, and intravenous excretory urography. Use of Optiray 350 and Optiray 320 in these age groups is based on controlled clinical trials involving 159 patients for pediatric angiocardiography; computed tomographic imaging of the head and body, and intravenous excretory urography. In general, the types of adverse reactions reported are similar to those of adults.

Safety and effectiveness of Optiray 240/300 have not been established in pediatric patients. Pediatric patients at higher risk of experiencing adverse reactions to Optiray include patients with: asthma, sensitivity to medication and/or allergens, congestive heart failure, serum creatinine greater than 1.5 mg/dL, or age less than 12 months. Thyroid function tests indicative of hypothyroidism or transient thyroid suppression have been uncommonly reported following iodinated contrast media administration in pediatric patients, including infants. Some patients were treated for hypothyroidism.

8.5 Geriatric Use

Ioversol is nearly completely excreted as parent drug by the kidney, and the risk of adverse reactions to Optiray may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, dose selection should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy

8.6 Renal Impairment

Ioversol is nearly completely excreted as parent drug by the kidney and renal impairment is expected to reduce the rate of elimination. Ioversol can be removed by dialysis.

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

PATIENT COUNSELING INFORMATION

PLR conversion, revised as below:

Hypersensitivity Reactions

Advise the patient concerning the risk of hypersensitivity reactions that can occur both during and after Optiray administration. Advise the patient to report any signs or symptoms of hypersensitivity reactions during the procedure and to seek medical attention for signs or symptoms experienced after discharge.

Advise patients to inform their physician if they develop a rash after receiving Optiray Contrast Induced Acute Kidney Injury

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

Extravasation

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

04/05/2017 (SUPPL-55)

Approved Drug Label (PDF)

5 Warnings and Precautions

WARNINGS

(additions underlined)

…

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 reactions. Avoid administering Optiray to patients with a history of a severe cutaneous adverse reaction to Optiray.

6 Adverse Reactions

General Adverse Reactions to Contrast Media

(additions 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)].

…

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

Information for Patients

(addition underlined)

Patients receiving iodinated intravascular contrast agents should be instructed to:

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 or food, or if you had any reactions to previous injections of dyes used for x-ray procedures.

4. Inform your physician about any other medications you are currently taking including non-prescription drugs.

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