PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - Optiray 300 PBP, 500 mL bottle

label

For Intravascular Use
Sterile Solution

---

** Optiray™ Pharmacy Bulk Package - 300**

---

500 mL
** NDC 0019-1332-61**

---

** IOVERSOL INJECTION 64%**
300 mg/mL Organically Bound Iodine

NOT FOR INTRATHECAL USE

Rx only

Pharmacy Bulk Package - Not for Direct Infusion

** Protect from light •** Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Discard contents if product is frozen or if crystallization occurs. Each mL contains 636 mg ioversol, 3.6 mg tromethamine as a buffer and 0.2 mg edetate calcium disodium as a stabilizer. The pH is adjusted with hydrochloric acid or sodium hydroxide.
Usual Dosage: See Package Insert for indications, dosage and dispensing information. Once bottle has been penetrated, withdrawal of contents should be completed without delay. Discard the container no later than 4 hours after initial entry.

12910419

Manufactured by:
Liebel-Flarsheim Company LLC
Raleigh, NC 27616
Made in USA

WARNING: NOT FOR INTRATHECAL USE

See full prescribing information for complete boxed warning.
Inadvertent intrathecal administration may cause death, convulsion, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

OPTIRAY is indicated for:

1.1 Intra-arterial

In adults

• OPTIRAY 320: cerebral arteriography, peripheral arteriography, visceral and renal arteriography, aortography, coronary arteriography, and left ventriculography.
• OPTIRAY 350: peripheral arteriography, coronary arteriography, and left ventriculography.

In pediatric patients

• OPTIRAY 320 and OPTIRAY 350: angiocardiography.

1.2 Intra-venous

In adults

• OPTIRAY 320: CT imaging of the head and body, venography, and intravenous excretory urography.
• OPTIRAY 350: CT imaging of the head and body, venography, intravenous excretory urography, and intravenous digital subtraction angiography (IV-DSA).

In pediatric patients

• OPTIRAY 320: CT imaging of the head and body, and intravenous excretory urography.

4 CONTRAINDICATIONS

Symptomatic hyperthyroidism.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Instructions

• OPTIRAY is for intravascular use only [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.1)].
• Use sterile technique for all handling and administration of OPTIRAY.
• Inspect glass container prior to use for breakage or other damage and do not use damaged containers.
• Warm OPTIRAY and administer at body or room temperature.
• Inspect OPTIRAY for particulate matter or discoloration before administration. Do not administer if OPTIRAY contains particulate matter or is discolored.
• Do not mix OPTIRAY with other drugs, solutions or total parenteral nutrition mixtures.
• Use the lowest dose necessary to obtain adequate visualization.
• Adjust the volume and concentration of OPTIRAY. Modify the dose accounting for factors such as age, body weight, vessel size, blood flow rate within the vessel, anticipated pathology, degree and extent of opacification required, structure(s) or area to be examined, disease processes affecting the patient, and equipment and technique to be employed.
• Avoid extravasation when injecting OPTIRAY; especially in patients with severe arterial or venous disease [see Warnings and Precautions (5.6)].
• Hydrate patients before and after OPTIRAY administration [see Warnings and Precautions (5.3)].

Directions for Proper Use of OPTIRAY Pharmacy Bulk Package

• The Pharmacy Bulk Package is not for direct infusion.
• Penetrate the container closure only one time, utilizing a suitable sterile transfer device or dispensing set which allows measured distribution of the contents.
• Transfer OPTIRAY from the Pharmacy Bulk Package only in a suitable work area, such as a laminar flow hood, utilizing aseptic technique.
• Withdraw container contents immediately. However, should this not be possible, a maximum time of 4 hours from initial closure entry is permitted to complete fluid transfer operations.
• Temperature of container after the closure has been entered should not exceed 25°C (77°F).

2.2 Intra-arterial Procedures in Adults

*Cerebral Arteriography

Use OPTIRAY 320. The recommended dose for visualization of cerebral arteries is shown below (may repeat as necessary):

Diagnostic area	Dose	Maximum Cumulative Dose
carotid or vertebral arteries	2 to 12 mL	200 mL
aortic arch injection (four vessel study)	20 to 50 mL	200 mL

*Peripheral Arteriography

Use OPTIRAY 320 or OPTIRAY 350. The recommended dose for visualization of peripheral arteries is shown below (may repeat as necessary):

Diagnostic area	Dose	Maximum Cumulative Dose
aorta-iliac runoff	60 mL (range 20 to 90 mL)	250 mL
common iliac, femoral	40 mL (range 10 to 50 mL)	250 mL
subclavian, brachial	20 mL (range 15 to 30 mL)	250 mL

*Visceral and Renal Arteriography and Aortography

Use OPTIRAY 320. The recommended dose for visualization for the aorta and visceral arteries is shown below (may repeat as necessary):

Diagnostic area	Dose	Maximum Cumulative Dose
aorta	45 mL (range 10 to 80 mL)	250 mL
celiac	45 mL (range 12 to 60 mL)	250 mL
superior mesenteric	45 mL (range 15 to 60 mL)	250 mL
renal or inferior mesenteric	9 mL (range 6 to 15 mL)	250 mL

*Coronary Arteriography and Left Ventriculography

Use OPTIRAY 320 or OPTIRAY 350. The recommended dose for visualization of the coronary arteries and left ventricle is shown below (may repeat as necessary):

Diagnostic area	Dose	Maximum Cumulative Dose
left coronary	8 mL (range 2 to 10 mL)	250 mL
right coronary	6 mL (range 1 to 10 mL)	250 mL
left ventricle	40 mL (range 30 to 50 mL)	250 mL

2.3 Intravenous Procedures in Adults

*Computed Tomography

Use OPTIRAY 320 or OPTIRAY 350 for head and body imaging.

Head Imaging
The recommended dosing is shown below:

• Scan immediately after completion of the intravenous administration.

	** Infusion**
OPTIRAY 320	50 to 150 mL
OPTIRAY 350	50 to 150 mL

Body Imaging
OPTIRAY may be administered by bolus injection, by rapid infusion, or by a combination of both. The recommended dosing is shown below:

• Scanning interval will vary with indication and target organ

	** Bolus Injection**	** Infusion**
OPTIRAY 320	25 to 75mL	50 to 150 mL
OPTIRAY 350	25 to 75mL	50 to 150 mL

*Venography

Use OPTIRAY 320 or OPTIRAY 350. The recommended dose is 50 to 100 mL per extremity; with a maximum cumulative dose of 250 mL.

*Intravenous Urography

Use OPTIRAY 350 or OPTIRAY 320. The recommended dose is shown below:

	** Usual Dose**	** High Dose Urography**	** Maximum Dose**
OPTIRAY 320	50 to 75mL	1.5 to 2 mL/kg	150 mL
OPTIRAY 350	50 to 75mL	1.4 mL/kg	150 mL

*Intravenous Digital Subtraction Angiography (IV-DSA)

Use OPTIRAY 350. The recommended dose range per injection is 30 to 50 mL; may repeat as necessary with a maximum cumulative dose of 250mL.

Injection rates will vary depending on the site of catheter placement and vessel size.

• Central catheter injections are usually made at a rate of between 10 and 30 mL/second.
• Peripheral injections are usually made at a rate of between 12 and 20 mL/second.

2.4 Pediatric Dosing

Intra-arterial Procedures

*Angiocardiography

Use OPTIRAY 350 or OPTIRAY 320. The recommended single ventricular dose is 1.25 mL/kg (range 1 mL/kg to 1.5 mL/kg). The maximum cumulative dose is 5 mL/kg up to a maximum total volume of 250 mL.

Intravenous Procedures

*Computed Tomography

Use OPTIRAY 320.

Head and Body Imaging
The recommended dose in pediatric patients is 1.5 mL/kg to 2 mL/kg (range 1 mL/kg to 3 mL/kg).

*Intravenous Urography

Use OPTIRAY 320. The recommended dose for pediatric patients is 1 mL/kg to 1.5 mL/kg (range 0.5 mL/kg to 3 mL/kg); with a maximum cumulative dose not exceeding 3 mL/kg.

3 DOSAGE FORMS AND STRENGTHS

Injection: clear, colorless to pale yellow solutions containing no undissolved solids, available in the following strengths and multiple-dose containers:

Imaging Product	mg of ioversol per mL	mg of organically bound iodine per mL	Pharmacy Bulk Pack Presentation
OPTIRAY 320 (Ioversol 68%)	678	320	Yes
OPTIRAY 350 (Ioversol 74%)	741	350	Yes

11 DESCRIPTION

11.1 Chemical Characteristics

OPTIRAY (ioversol injection) is a non-ionic radiographic contrast agent. OPTIRAY formulations are sterile, nonpyrogenic, aqueous solutions intended for intravascular use. Each bottle is to be used as a Pharmacy Bulk Package for dispensing multiple single dose preparations utilizing a suitable transfer device. Ioversol is designated chemically as N,N'-Bis (2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl) -glycolamido] -2,4,6-triiodoisophthalamide. The molecular weight of ioversol is 807.11 and the organically bound iodine content is 47.2%.
The structural formula of ioversol is as follows:


OPTIRAY Pharmacy Bulk Package is available in two strengths:

• OPTIRAY 320 (ioversol injection 68%): Each mL contains 320 mg organically bound iodine, 678 mg of ioversol, 3.6 mg tromethamine, 0.2 mg edetate calcium disodium.

• OPTIRAY 350 (ioversol injection 74%): Each mL contains 350 mg organically bound iodine, 741 mg ioversol, 3.6 mg tromethamine, 0.2 mg edetate calcium disodium.

The pH of the OPTIRAY formulations has been adjusted to 6.0 to 7.4 with hydrochloric acid or sodium hydroxide. All solutions are sterilized by autoclaving and contain no preservatives. Ioversol does not dissociate in solution.

11.2 Physical Characteristics

Some physical and chemical properties of these formulations are listed below:

	OPTIRAY 320	OPTIRAY 350
Ioversol content (mg/mL)	678	741
Iodine content (mg l/mL)	320	350
Osmolality (mOsm/kg water)	702	792
Viscosity (cps)
at 25°C	9.9	14.3
at 37°C	5.8	9.0
Specific Gravity at 37°C	1.371	1.405

The OPTIRAY formulations are clear, colorless to pale yellow solutions containing no undissolved solids. Crystallization does not occur at room temperature. OPTIRAY solutions have osmolalities 2.3 to 2.8 times that of plasma (285 mOsm/kg water) as shown in the above table and are hypertonic under conditions of use.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long term animal studies have been performed to evaluate carcinogenic potential. Nonclinical studies show that this drug is not mutagenic and does not affect fertility.

13.2 Animal Toxicology and/or Pharmacology

Animal studies indicate that ioversol does not cross the blood-brain barrier.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

OPTIRAY is a clear, colorless to pale yellow, sterile, pyrogen-free, aqueous solution available in two strengths. The products are supplied in containers from which the air has been displaced by nitrogen. OPTIRAY is supplied in the following configurations:

** NDC Number**

OPTIRAY Pharmacy Bulk Package - 350

6x500 mL Pharmacy Bulk Packages 0019-1333-61

OPTIRAY Pharmacy Bulk Package - 320

6x500 mL Pharmacy Bulk Packages 0019-1323-61

16.2 Storage

• Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).
• Protect from strong daylight or direct exposure to the sun.
• Discard OPTIRAY containers, and their contents, if they are frozen or if crystallization occurs.

17 PATIENT COUNSELING INFORMATION

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 [see Warnings and Precautions (5.2)].

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

Contrast Induced 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 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)].

Manufactured by:
Liebel-Flarsheim Company LLC
Raleigh, NC 27616

Made in USA


GBT 13PB825

8 USE IN SPECIFIC POPULATIONS

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 [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.

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 Day7 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 contrast enhanced 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; contrast enhanced 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 [see Adverse Reactions (6.1)].

Safety and effectiveness of OPTIRAY 350 and OPTIRAY 320 have not been established in pediatric patients less than 1 month of age.

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 [See Adverse Reactions (6.2)].

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. 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)].

8.5 Geriatric Use

OPTIRAY is substantially excreted 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

In patients with impaired renal function, the elimination half-life is prolonged. Ioversol can be removed by dialysis.