ADVERSE EVENTS REPORTED IN CONTROLLED CLINICAL TRIALS IN GREATER THAN 0.5% OF 1,244 ADULT PATIENTS RECEIVING IODIXANOL OR OTHER IODINATED CONTRAST AGENTS
NUMBER OF PATIENTS EXPOSED	Iodixanol N (%)= 1,244	Pooled Comparators N (%) = 861
Number of Patients with Any Adverse Event	248 (19.9)	194 (22.5)
Body As a Whole	Patients With Any Event	41 (3.3)	22 (2.6)
Edema (any location)	7 (0.6)	0 (0)
Cardiovascular	Patients With Any Event	37 (3.0)	39 (4.5)
Angina Pectoris/Chest Pain	28 (2.2)	22 (2.6)
Gastrointestinal	Patients With Any Event	51 (4.1)	46 (5.3)
Diarrhea	7 (0.6)	6 (0.7)
Nausea	35 (2.8)	32 (3.7)
Vomiting	10 (0.8)	11 (1.3)
Nervous System	Patients With Any Event	101 (8.1)	60 (7.0)
Agitation, Anxiety, Insomnia, Nervousness	10 (0.8)	0 (0)
Dizziness	8 (0.7)	8 (0.9)
Headache/Migraine	31 (2.5)	15 (1.7)
Paresthesia	12 (1.0)	1 (0.1)
Sensory Disturbance	10 (0.8)	9 (1.0)
Syncope	8 (0.6)	1 (0.1)
Vertigo	30 (2.4)	20 (2.3)
Skin (not including application site)	Patients With Any Event	42 (4.6)	18 (2.1)
Nonurticarial Rash or Erythema	26 (2.1)	4 (0.5)
Pruritus	20 (1.6)	3 (0.3)
Urticaria	6 (0.5)	10 (1.2)
Special Senses	Patients With Any Event	57 (4.6)	38 (4.4)
Parosmia	6 (0.5)	4 (0.5)
Taste Perversion	43 (3.5)	32 (3.7)
Scotoma	14 (1.1)	2 (0.2)

MEAN ELIMINATION HALF-LIFE* IN PEDIATRIC PATIENTS
Age Range	Number of Patients	Elimination half-life
Newborn to < 2 months	8	4.1 ± 1.4
2 to 6 months	8	2.8 ± 0.6
6 to 12 months	9	2.4 ± 0.4
1 to 2 years	5	2.3 ± 0.6
2 to 12 years	10	2.3 ± 0.5
Adults	40	2.1 ± 0.1

For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids:
Cortisone, 25	Triamcinolone, 4
Hydrocortisone, 20	Paramethasone, 2
Prednisolone, 5	Betamethasone, 0.75
Prednisone, 5	Dexamethasone, 0.75
Methylprednisolone, 4

Recommended Doses for Intra-articular Injection
Size of Joint	Location	Dose (mL)
Very Large	Hip	1 - 2
Large	Knee, ankle, shoulder	1
Medium	Elbow, wrist	0.5 - 1
Small (metacarpophalangeal, interphalangeal) (sternoclavicular)	Hand, chest	0.25 to 0.5

Diagnosis	Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension Dose (mL)
Bursitis under heloma durum or heloma molle	0.25 to 0.5
under calcaneal spur	0.5
over hallux rigidus or digiti quinti varus	0.5
Tenosynovitis, periostitis of cuboid	0.5
Acute gouty arthritis	0.5 to 1

BL-C Kit Dailymed

Generic: betamethasone sodium phosphate, betamethasone acetate, lidocaine, iodixanol, povidine iodine is used for the treatment of Dermatitis, Atopic Facial Dermatoses Foot Dermatoses Hand Dermatoses Inflammation Leg Dermatoses Mycoses Pruritus Ani Psoriasis Scalp Dermatoses Dermatitis, Seborrheic Purpura, Thrombocytopenic, Idiopathic

Boxed Warning

Warning: Not For Intrathecal Use

Inadvertent intrathecal administration may cause death, convulsions/seizures, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, rhabdomyolysis, hyperthermia, and brain edema [see Contraindications ( 4) and Adverse Reactions ( 5.1)] . WARNING: NOT FOR INTRATHECAL USE See full prescribing information for complete boxed warning Inadvertent intrathecal administration may cause death, convulsions/seizures, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, rhabdomyolysis, hyperthermia, and brain edema. ( 4 , 5.1 )

FDA Adverse Reactions

Go PRO for all pill images

Warning: Not For Intrathecal Use

Inadvertent intrathecal administration may cause death, convulsions/seizures, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, rhabdomyolysis, hyperthermia, and brain edema [see Contraindications ( 4) and Adverse Reactions ( 5.1)] .

WARNING: NOT FOR INTRATHECAL USE See full prescribing information for complete boxed warning Inadvertent intrathecal administration may cause death, convulsions/seizures, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, rhabdomyolysis, hyperthermia, and brain edema. ( 4 , 5.1 )

Recent Major Changes Section

Warnings and Precautions, Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age ( 5.8) 04/2023

1 Indications And Usage

Iodixanol injection is indicated in for:

Iodixanol injection is a radiographic contrast agent indicated for the following: Intra-arterial Procedures( 1.1) Adults and pediatric patients 12 years of age and over

Intra-arterial digital subtraction angiography (270 mg Iodine/mL and 320 mg Iodine/mL).

Angiocardiography (left ventriculography and selective coronary arteriography), peripheral arteriography, visceral arteriography, and cerebral arteriography (320 mg Iodine/mL).

Pediatric patients less than 12 years of age

Angiocardiography, cerebral arteriography, and visceral arteriography (320 mg Iodine/mL).

Intravenous Procedures( 1.2) Adults and pediatric patients 12 years of age and over

Computed tomography (CT) imaging head and body (270 mg Iodine/mL and 320 mg Iodine/mL).

Excretory urography (270 mg Iodine/mL and 320 mg Iodine/mL).

Peripheral venography (270 mg Iodine/mL).

Coronary computed tomography angiography (CCTA) to assist diagnostic evaluation of patients with suspected coronary artery disease (320 mg Iodine/mL).

Pediatric patients less than 12 years of age

CT imaging of the head and body (270 mg Iodine/mL).

Excretory urography (270 mg Iodine/mL).

1.1 Intra-arterial Procedures

Adult and pediatric patients 12 years of age and older

(270 mg Iodine/mL and 320 mg Iodine/mL) intra-arterial digital subtraction angiography (IA-DSA).

(320 mg Iodine/mL) angiocardiography (left ventriculography and selective coronary arteriography), peripheral arteriography, visceral arteriography, and cerebral arteriography.

Pediatric patients less than 12 years of age

(320 mg Iodine/mL) angiocardiography, cerebral arteriography, and visceral arteriography.

1.2 Intravenous Procedures

Adult and pediatric patients 12 years of age and older

(270 mg Iodine/mL and 320 mg Iodine/mL) CT imaging of the head and body.

(270 mg Iodine/mL and 320 mg Iodine/mL) excretory urography.

(270 mg Iodine/mL) peripheral venography.

(320 mg Iodine/mL) coronary computed tomography angiography (CCTA) to assist in the diagnostic evaluation of patients with suspected coronary artery disease.

Pediatric patients less than 12 years of age

(270 mg Iodine/mL) CT imaging of the head and body.

(270 mg Iodine/mL) excretory urography.

2 Dosage And Administration

Individualize the combination of volume and concentration of iodixanol injection considering age, body weight, size of the vessel, rate of blood flow within the vessel, and other applicable factors. ( 2.1, 2.2, 2.3, 2.4)

For CT of the head and body, iodixanol injection may be used with an automated contrast injection system or contrast media management system cleared for use with iodixanol injection. (2.5)

For the adult patients, the maximum recommended total dose of iodine is 80 grams. ( 2.1)

Patients should be adequately hydrated prior to and following the intravascular administration of iodinated contrast agents. ( 2.1, 5.3)

See full prescribing information for complete dosing and administration information. (2)

2.1 Important Dosage and Administration Instructions

Iodixanol injection is for intravascular use only [see Boxed Warning, Contraindications (4), and Warnings and Precautions (5.1)]

Use sterile technique for all handling and administration of iodixanol injection.

Do not use if tamper-evident ring is broken or missing.

Warm iodixanol injection and administer at body or room temperature.

Inspect iodixanol injection for particulate matter or discoloration before administration, whenever solution and container permit. Do not administer if iodixanol injection contains particulate matter or is discolored.

Do not mix iodixanol injection with, or inject in intravenous lines containing, other drugs or total nutritional admixtures.

Use the lowest dose necessary to obtain adequate visualization.

Individualize the volume, strength, and rate of administration of iodixanol injection. Consider factors such as age, bodyweight, vessel size, blood flow rate within the vessel, anticipated pathology, degree and extent of opacification required, structures or area to be examined, disease processes affecting the patient, and equipment and technique to be employed.

The maximum recommended total dose of iodine for adults is 80 grams.

Avoid extravasation when injecting iodixanol injection; especially in patients with severe arterial or venous disease [see Warnings and Precautions (5.6) ].

Hydrate patients before and after iodixanol injection administration [see Warnings and Precautions (5.3)] .

2.2 Intra-arterial Dosage and Administration

Intra-arterial digital subtraction angiography (IA-DSA)(270 mg Iodine/mL and 320 mg Iodine/mL)

Angiocardiography (left ventriculography and selective coronary arteriography), peripheral arteriography, visceral arteriography, and cerebral arteriography(320 mg Iodine/mL)

Use injection rates approximately equal to the flow rate in the vessel being injected. The usual single injection volumes or total dose per patient (mL/kg) for adults and adolescents over 12 years of age are uled in Table 1:

TABLE 1

ADULTS and PEDIATRIC PATIENTS 12 YEARS OF AGE AND OLDER

IODIXANOL INJECTION SINGLE DOSE RECOMMENDATIONS FOR INJECTION INTO SELECTED ARTERIES

ARTERIOGRAPHY

IA-DSA1

Maximum Total Dose

Intra-arterial Injection Sites

320 mg Iodine/mL

270 mg Iodine/mL

320 mg Iodine/mL

Carotid Arteries

10 mL to 14 mL

5 mL to 8 mL

Usually Not to Exceed 175 mL

Vertebral Arteries

10 mL to 12 mL

5 mL to 8 mL

Right Coronary Artery

3 mL to 8 mL

Usually Not to Exceed 200 mL

Left Coronary Artery

3 mL to 10 mL

Left Ventricle

20 mL to 45 mL

Renal Arteries

8 mL to 18 mL

10 mL to 25 mL

--

Usually Not to Exceed 250 mL

Aortography

30 mL to 70 mL

20 mL to 50 mL

10 mL to 50 mL

Major Branches of Aorta

10 mL to 70 mL

5 mL to 30 mL

2 mL to 10 mL

Aortofemoral Runoffs

20 mL to 90 mL

--

6 mL to 15 mL

Peripheral Arteries

15 mL to 30 mL

--

3 mL to 15 mL

1 IA-DSA = Intra-arterial Digital Subtraction Angiography

2.3 Intravenous Dosage and Administration

Computed Tomography of the Head or Body(270 mg Iodine/mL and 320 mg Iodine/mL)

Excretory Urography(270 mg Iodine/mL and 320 mg Iodine/mL)

Peripheral Venography(270 mg Iodine/mL)

Coronary Computed Tomography Angiography (CCTA)(320 mg Iodine/mL)

Recommended dosage of iodixanol injection is dependent on: the administration procedure, patient weight, and CT device factors, as detailed in Table 2. Calibrate the intravenous injection rate so that image acquisition coincides with peak arterial concentration. The time between iodixanol injection and peak arterial concentration varies between patients. Selected dosing for different indications in adults and pediatric patients over 12 years of age are shown in Table 2.

TABLE 2

ADULTS and PEDIATRIC PATIENTS 12 YEARS OF AGE AND OLDER IODIXANOL INJECTION DOSING RECOMMENDATIONS FOR INTRAVENOUS CONTRAST ADMINISTRATION

Study Type Comment 270 mg Iodine/mL 320 mg Iodine/mL Maximum Total Volume

CT of Head or Body ¹
Bolus
75 mL to 150 mL 75 mL to 150 mL 150 mL

Infusion 100 mL to 150 mL 100 mL to 150 mL

Excretory Urography Normal Renal Function 1 mL/kg 1 mL/kg 100 mL

Venography Per lower extremity 50 mL to 150 mL 250 mL

CCTA ^1,2 Bolus injection with test bolus ³ or bolus tracking 50 mL to 150 mL ⁴ (4 mL to 7 mL per second) 150 mL

¹For CT of the head and body, iodixanol injection may be used with an automated contrast injection system or contrast media management system cleared for use with iodixanol injection.

²For pediatric patients aged 12 to 17, recommended dose is 1 mL/kg to 2 mL/kg. ³The main iodixanol injection volume may be preceded by a test bolus consisting of 20 mL iodixanol injection, immediately followed by a 20 mL saline flush, both injected at rate of 4 mL/sec to 7 mL/sec. ⁴Injection of iodixanol injection with saline can be either biphasic (without dilution phase) or triphasic (with dilution phase). Alternatively, a dose of 1 mL/kg may be used to calculate total iodixanol injection dose (excluding any test bolus). For CCTA acquired at < 120 kVp, the dose of iodixanol injection may be reduced by up to 15% in patients < 85 kg and BMI < 30 kg/m ². For CCTA acquired on a scanner with more than 64 detector rows, the dose of iodixanol injection may be reduced in proportion to the scan duration.

2.4 Dosage in Pediatric Patients Less Than 12 Years of Age

Intra-arterial Dosage and Administration

Angiocardiography, cerebral arteriography, or visceral arteriography(320 mg Iodine/mL): The recommended dosage is 1 mL/kg to 2 mL/kg. The maximum dose should not exceed 4 mL/kg.

Intravenous Dosage and Administration Computerized Tomography or Excretory Urography(270 mg Iodine/mL): The recommended dosage is 1 mL/kg to 2 mL/kg. The maximum dose should not exceed 2 mL/kg.

2.5 Instructions for Use with an Automated Contrast Injection System or Contrast Management System for CT of the Head and Body

Iodixanol injection may be used with an automated contrast injection system cleared for use with contrast media.

◦ See above Important Dosage and Administration Instructions for iodixanol injection (2.1).

◦ See device labeling for information on device indications, instructions for use, and techniques to help assure safe use.

Iodixanol injection 320 mg Iodine/mL in 100 mL and 150 mL bottles may be used with a contrast media management system cleared for use with iodixanol injection 320 mg Iodine/mL in 100 mL and 150 mL bottles.

◦ See device labeling for information on device indications, instructions for use, and techniques to help assure safe use.

◦ Use sterile technique for penetrating the container closure of iodixanol injection 320 mg Iodine/mL and transferring iodixanol injection solution. Clean the stopper with a pad soaked in sporicidal solution followed by a pad soaked in alcohol, then puncture the stopper. The container closure may be penetrated only one time with a suitable sterile component of the contrast media management system cleared for use with iodixanol injection 320 mg Iodine/mL in 100 mL and 150 mL bottles.

◦ Once the iodixanol injection 320 mg Iodine/mL is punctured do not remove the bottle from the work area during the entire period of use.

◦ Maximum use time is 4 hours after initial puncture.

◦ Each bottle is for one procedure only. Discard unused portion.

3 Dosage Forms And Strengths

Injection: Non-ionic, isotonic, water-soluble, sterile, pyrogen-free, colorless to pale yellow solution in the following strengths:

270 mg of organically bound iodine per mL (550 mg Iodixanol per mL).

320 mg of organically bound iodine per mL (652 mg Iodixanol per mL).

Available in the following format: Single-dose polypropylene bottle.

Injection: In concentrations of 270 mg and 320 mg of organically bound iodine per mL (550 mg and 652 mg of Iodixanol per mL). ( 3)

4 Contraindications

Iodixanol is contraindicated for intrathecal use [see Warnings and Precautions (5.1)] :

Not indicated for intrathecal use. ( 4)

5 Warnings And Precautions

Hypersensitivity Reactions: Life-threatening or fatal reactions can occur. Always have emergency equipment and trained personnel available. ( 5.2)

Contrast-Induced Acute Kidney Injury: Acute injury including renal failure can occur. Minimize dose and maintain adequate hydration to minimize risk. ( 5.3)

Cardiovascular Adverse Reactions: Hemodynamic disturbances including shock and cardiac arrest may occur during or after administration. ( 5.4)

Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age: Individualize thyroid function monitoring based on risk factors such as prematurity. ( 5.8)

5.1 Risks Associated with Inadvertent Intrathecal Administration

Iodixanol is for intravascular use only and is contraindicated for intrathecal use [see Contraindications (4)and Dosage and Administration (2.1)] . Inadvertent Intrathecal administration can cause death, convulsions/seizures, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, rhabdomyolysis, hyperthermia, and brain edema.

5.2 Hypersensitivity Reactions

Iodixanol can cause life-threatening or fatal hypersensitivity reactions including anaphylaxis. Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock. Most severe reactions develop shortly after the start of the injection (within 3 minutes), but reactions can occur up to hours later. 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) 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 always have emergency resuscitation equipment and trained personnel available prior to iodixanol administration. Monitor all patients for hypersensitivity reactions.

5.3 Contrast-Induced Acute Kidney Injury

Acute kidney injury, including renal failure, may occur after iodixanol 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 iodixanol in patients with renal impairment. Adequately hydrate patients prior to and following iodixanol administration. Do not use laxatives, diuretics, or preparatory dehydration prior to iodixanol administration.

5.4 Cardiovascular Adverse Reactions

Life-threatening or fatal cardiovascular reactions including hypotension, shock, cardiac arrest have occurred with the use of iodixanol. Most deaths occur during injection or five to ten minutes later, with cardiovascular disease as the main aggravating factor. Cardiac decompensation, serious arrhythmias, and myocardial ischemia or infarction can occur during coronary arteriography and ventriculography.

Based upon clinical literature reported deaths from the administration of iodinated contrast agents range from 6.6 per million (0.00066%) to 1 in 10,000 (0.01%). Use the lowest necessary dose of iodixanol 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 Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke can occur during angiocardiography procedures with both ionic and nonionic contrast media. 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 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 angiocardiography in patients with homocystinuria because of the risk of inducing thrombosis and embolism.

5.6 Extravasation and Injection Site Reactions

Extravasation of iodixanol injection may cause tissue necrosis and/or compartment syndrome, particularly in patients with severe arterial or venous disease. 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

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 iodixanol.

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 (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.

5.9 Hypertensive Crisis in Patients with Pheochromocytoma

Hypertensive crisis has occurred after the use of iodinated contrast agents in patient with pheochromocytoma. Monitor patients when administering iodixanol if pheochromocytoma or catecholamine-secreting paragangliomas are suspected. Inject the minimum amount of contrast necessary, assess the blood pressure throughout the procedure, and have measures for treatment of a hypertensive crisis readily available.

5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease

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

5.11 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 agents; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering iodixanol to patients with a history of a severe cutaneous adverse reaction to iodixanol.

6 Adverse Reactions

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

Risks Associated with Inadvertent Intrathecal Administration [see Warnings and Precautions (5.1)]

Hypersensitivity Reactions [see Warnings and Precautions (5.2)]

Contrast-Induced Kidney Injury [see Warnings and Precautions (5.3)]

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

Thromboembolic Events [see Warnings and Precautions (5.5)]

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)]

Most common adverse reactions (incidence greater than 0.5%) in adult patients after iodixanol injection: Discomfort, warmth, pain; Cardiovascular: angina. Gastrointestinal: diarrhea, nausea, vomiting. Nervous System: agitation, anxiety, insomnia, nervousness, dizziness, headache, migraine, unusual skin sensations, sensory disturbance, fainting, sensation of spinning. Skin: itchy rash, severe itching, hives. Special Senses: Smell, taste, and vision alteration. ( 6.1) Pediatric patients experienced similar adverse reactions. ( 6.3)

To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

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.

Iodixanol is often associated with sensations of discomfort, warmth or pain. In a subgroup of 1,259 patients; 30% who received iodixanol or a comparator had application site discomfort, pain, warmth or cold. Iodixanol had a trend toward fewer patient reports of moderate or severe pain or warmth. Pain was reported in 2% of patients receiving iodixanol and 10% of patients receiving a comparator. Heat was reported in 29% of patients receiving iodixanol and 51% of patients receiving a comparator.

Table 3 shows the incidence of events reported in blinded, controlled clinical studies of iodixanol in a total of 1,244 adult patients. Adverse events (AEs) are uled by body system and in decreasing order of occurrence greater than 0.5% of patients. One or more adverse events were reported in 20% of patients during the study period (24 to 72 hours). In a 757 patient subgroup, the number of women reporting adverse events was 83/299 (28%) and the number of men was 77/458 (16%). A total of 3% of women and 0.8% of men reported chest pain.

TABLE 3

ADVERSE EVENTS REPORTED IN CONTROLLED CLINICAL TRIALS IN GREATER THAN 0.5% OF 1,244 ADULT PATIENTS RECEIVING IODIXANOL OR OTHER IODINATED CONTRAST AGENTS

NUMBER OF PATIENTS EXPOSED Iodixanol N (%)= 1,244 Pooled Comparators N (%) = 861

Number of Patients with Any Adverse Event 248 (19.9) 194 (22.5)

Body As a Whole Patients With Any Event 41 (3.3) 22 (2.6)

Edema (any location) 7 (0.6) 0 (0)

Cardiovascular Patients With Any Event 37 (3.0) 39 (4.5)

Angina Pectoris/Chest Pain 28 (2.2) 22 (2.6)

Gastrointestinal Patients With Any Event 51 (4.1) 46 (5.3)

Diarrhea 7 (0.6) 6 (0.7)

Nausea 35 (2.8) 32 (3.7)

Vomiting 10 (0.8) 11 (1.3)

Nervous System Patients With Any Event 101 (8.1) 60 (7.0)

Agitation, Anxiety, Insomnia, Nervousness 10 (0.8) 0 (0)

Dizziness 8 (0.7) 8 (0.9)

Headache/Migraine 31 (2.5) 15 (1.7)

Paresthesia 12 (1.0) 1 (0.1)

Sensory Disturbance 10 (0.8) 9 (1.0)

Syncope 8 (0.6) 1 (0.1)

Vertigo 30 (2.4) 20 (2.3)

Skin (not including application site) Patients With Any Event 42 (4.6) 18 (2.1)

Nonurticarial Rash or Erythema 26 (2.1) 4 (0.5)

Pruritus 20 (1.6) 3 (0.3)

Urticaria 6 (0.5) 10 (1.2)

Special Senses Patients With Any Event 57 (4.6) 38 (4.4)

Parosmia 6 (0.5) 4 (0.5)

Taste Perversion 43 (3.5) 32 (3.7)

Scotoma 14 (1.1) 2 (0.2)

The following selected adverse events were reported in ≤0.5% of the 1,244 patients.

Body as a Whole—General Disorders: back pain, fatigue, malaise

Cardiovascular Disorders: arrhythmias, cardiac failure, conduction abnormalities, hypotension, myocardial infarction

Gastrointestinal System Disorders: dyspepsia

Hypersensitivity Disorders: pharyngeal edema

Nervous System: cerebral vascular disorder, convulsions, hypoesthesia, stupor, confusion

Peripheral Vascular Disorders: flushing, peripheral ischemia

Renal System Disorders: abnormal renal function, acute renal failure, hematuria

Respiratory System Disorders: asthma, bronchitis, dyspnea, pulmonary edema, rhinitis

Skin and Appendage Disorders: hematoma, increased sweating

Special Senses, Other Disorders: tinnitus

Vision Disorders: abnormal vision

6.2 Post-marketing Experience

The following additional adverse reactions have been identified during post approval use of iodixanol. 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 exposure.

Cardiovascular Disorders:Cardiac arrest, palpitations, spasms of coronary arteries, hypertension, and flushing

Endocrine Disorders:Hyperthyroidism, hypothyroidism

Eye Disorders:Transient visual impairment including cortical blindness, diplopia, and blurred vision

Gastrointestinal Disorders:Abdominal pain, pancreatitis, salivary gland enlargement

General Disorders and Administration Site Conditions:Chills, pyrexia, pain and discomfort, administration site reactions including extravasation

Immune System Disorders:Hypersensitivity reactions, anaphylactic shock including, life-threatening or fatal anaphylaxis

Nervous System Disorders:Tremor (transient), coma, disturbance in consciousness, transient contrast-induced encephalopathy caused by extravasation of contrast media (including amnesia, hallucination, paralysis, paresis, transient speech disorder, aphasia, dysarthria)

Psychiatric Disorders:Anxiety, agitation

Respiratory, Thoracic, and Mediastinal Disorders:Cough, sneezing, throat irritation or tightness, laryngeal edema, pharyngeal edema, bronchospasm

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)]

6.3 Pediatric Adverse Reactions

The overall character, quality, and severity of adverse reactions in pediatric patients is similar to that reported in adult patients from post marketing surveillance and other information.

Additional safety data was obtained in studies of iodixanol in 459 pediatric patients. A total of 26 patients ranged in age from birth to <29 days, 148 ranged from 29 days to 2 years, 263 from 2 to <12 years, and 22 from 12 to 18 years. A total of 252 (55%) of the patients were male. The racial distribution was: Caucasian-81%, Black-14%, Oriental-2%, and other or unknown-4%. The proportion of patients undergoing an intra-arterial procedure by age was: 92 % (<29 days), 55% (29 days to 6 months), and 29 % (>6 months). In these studies, adverse events were numerically higher in pediatric patients less than one year of age compared to older pediatric patients.

In pediatric patients who received intravenous injections of iodixanol for computerized tomography or excretory urography, a concentration of 270 mg Iodine/mL was used in 144 patients, and a concentration of 320 mg Iodine/mL in 154 patients. All patients received one intravenous injection of 1 mL/kg to 2 mL/kg.

In pediatric patients who received intra-arterial and intracardiac studies, a concentration of 320 mg Iodine/mL was used in 161 patients. Twenty-two patients were <29 days of age; 78 were 29 days to 2 years of age; and 61 were over 2 years. Most of these pediatric patients received initial volumes of 1 mL/kg to 2 mL/kg and most patients received a maximum of 3 injections.

7 Drug Interactions

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, iodixanol administration in patients with an eGFR between 30 mL/min/1.73 m ²and 60 mL/min/1.73 m ²; in patients with a history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and reinstitute metformin only after renal function is stable.

Radioactive Iodine

Administration of iodinated contrast agents may interfere with thyroid uptake of radioactive iodine (I-131 and I-123) and decrease therapeutic and diagnostic efficacy in patients with carcinoma of the thyroid. The decrease in efficacy lasts for 6 to 8 weeks.

Beta-adrenergic Blocking Agents

The use of beta-adrenergic blocking agents lowers the threshold for and increases the severity of contrast reactions, and reduces the responsiveness of treatment of hypersensitivity reactions with epinephrine. Because of the risk of hypersensitivity reactions, use caution when administering iodixanol to patients taking beta-blockers.

Oral Cholecystographic Contrast Agents

Renal toxicity has been reported in patients with liver dysfunction who were given an oral cholecystographic agent followed by intravascular iodinated contrast agents. Postpone the administration of iodixanol in patients who have recently received an oral cholecystographic contrast agent.

7.2 Drug-Laboratory Test Interactions

Effect on Thyroid Tests

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

Effect on Urine Tests

As reported with other contrast agents, iodixanol may produce a false-positive result for protein in the urine using urine dip tests. However, the Coomassie blue method has been shown to give accurate results for the measurement of urine protein in the presence of iodixanol. In addition, care should be used in interpreting the results of urine specific gravity measurements in the presence of high levels of iodixanol and other contrast agents in the urine. Refractometry or urine osmolality may be substituted.

8 Use In Specific Populations

Lactation: A lactating woman may pump and discard breast milk for 10 hours after iodixanol administration. ( 8.2)

Geriatrics: Exercise caution in dose selection for elderly patients. ( 8.5)

8.1 Pregnancy

Risk Summary

There are no data with iodixanol use in pregnant women to inform any drug-associated risks. In animal reproduction studies, no developmental toxicity occurred with intravenous iodixanol administration to rats and rabbits at doses up to 0.24 (rat) or 0.48 (rabbit) times the maximum recommended human intravenous dose (see Data).

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

Animal Data

Reproduction studies were performed in rats and rabbits with intravenous administration of iodixanol at doses up to 2 g Iodine/kg, daily, from implantation of the embryo (gestation day 7 in rat; 6 in rabbit) through closure of the hard palate (gestation day 17 in rats; 18 in rabbits). No maternal toxicity occurred, and no adverse effects occurred on fetal survival, embryo-fetal development, or the ability of dams to rear a litter.

8.2 Lactation

Risk Summary

There are no data on the presence of iodixanol 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 iodixanol and any potential adverse effects on the breastfed infant from iodixanol 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 elimination half-lives) after iodixanol administration in order to minimize drug exposure to a breast fed infant.

8.4 Pediatric Use

The safety and efficacy of iodixanol have been established in pediatric patients down to birth for angiocardiography, cerebral arteriography, visceral arteriography, CT imaging of the head and body, and excretory urography. The safety and efficacy of iodixanol have also been established in pediatric patients 12 years and older for intra-arterial digital subtraction angiography, peripheral arteriography, peripheral venography and CCTA. Use of iodixanol is supported by evidence from adequate and well controlled studies of iodixanol in adults and additional safety data obtained in 459 pediatric patients. In general, the types of adverse reactions reported are similar to those of adults. A higher number of adverse events in patients less than 1 year of age compared to older patients were observed in a study of iodixanol [see Adverse Events (6.3)] . The elimination of iodixanol is slower in this age group [see Clinical Pharmacology (12.3)] .

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)] .

Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent may include those with asthma, hypersensitivity to other medication and/or allergens, cyanotic and acyanotic heart disease, congestive heart failure, or a serum creatinine greater than 1.5 mg/dL. Pediatric patients with immature renal function or dehydration may be at increased risk for adverse events due to slower elimination of iodinated contrast agents [see Clinical Pharmacology (12.3)] .

8.5 Geriatric Use

In clinical studies of iodixanol, 254/757 (34%) of patients were 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient 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.

10 Overdosage

The adverse effects of overdosage of any contrast agent may be life-threatening and affect mainly the pulmonary and cardiovascular systems. Treatment of an overdosage is directed toward the support of all vital functions and prompt institution of symptomatic therapy. Iodixanol injection does not bind to plasma or serum protein and can be dialyzed.

11 Description

11.1 Chemical Characteristics

Iodixanol injection, USP is a dimeric, iso-osmolar, nonionic, water-soluble, radiographic contrast medium for intravascular (intravenous and intra-arterial) use. It is provided as a ready-to-use sterile, pyrogen-free, and preservative free, colorless to pale yellow solution.

The chemical formula is 5,5´-[(2-hydroxy-1,3-propanediyl) bis(acetylimino)] bis[N,N´-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide] with a molecular weight of 1,550.18 (iodine content 49.1%).

Iodixanol (C ₃₅H ₄₄I ₆N ₆O ₁₅) has the following structural formula:

Iodixanol injection, USP is available in two strengths:

Iodixanol Injection, USP, 270 mg Iodine/mL (550 mg Iodixanol/mL), 0.074 mg calcium chloride dihydrate, 1.87 mg sodium chloride, 1.2 mg tromethamine, and 0.1 mg edetate calcium disodium.

Iodixanol Injection, USP, 320 mg Iodine/mL (652 mg Iodixanol/mL), 0.044 mg calcium chloride dihydrate, 1.11 mg sodium chloride, 1.2 mg tromethamine and 0.1 mg edetate calcium disodium.

Sodium chloride and calcium chloride have been added, resulting in an isotonic solution for injection providing for both concentrations a sodium/calcium ratio equivalent to blood.

The pH is adjusted to 7.4 with hydrochloric acid and/or sodium hydroxide to achieve a range between pH 6.8 and 7.7 at 22°C.

11.2 Physical Characteristics

The two concentrations of iodixanol injection, USP (270 mg Iodine/mL and 320 mg Iodine/mL) have the following physical properties: TABLE 4

Physical Properties of Iodixanol Injection, USP

Parameter Concentration (mg Iodine/mL)

320 270

Osmolality (mOsmol/kg water) 290 290

Viscosity (cP) @ 20°C 26.6 12.7

@ 37°C 11.8 6.3

Density (g/mL) @ 20°C 1.369 1.314

@ 37°C 1.356 1.303

12 Clinical Pharmacology

12.1 Mechanism of Action

Intravascular injection of iodixanol opacifies vessels in the path of flow of the contrast agent, permitting visualization of internal structures.

In imaging of the body, iodinated contrast agents diffuse from the vascular into the extravascular space. In a normal brain with an intact blood-brain barrier, contrast does not diffuse into the extravascular space. In patients with a disrupted blood- brain barrier, contrast agent accumulates in the interstitial space in the region of disruption.

12.2 Pharmacodynamics

Following administration of iodixanol, the degree of enhancement is directly related to the iodine content in an administered dose. Peak iodine plasma levels occur immediately following rapid injection. The time to maximum contrast enhancement can vary, depending on the organ, from the time that peak blood iodine concentrations are reached to one hour after intravenous bolus administration. When a delay between peak blood iodine concentrations and peak contrast is present, it suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine-containing medium within the lesion and outside the blood pool.

For angiography, contrast enhancement is greatest immediately (15 seconds to 120 seconds) after rapid injection. Iodinated contrast agents may be visualized in the renal parenchyma within 30 to 60 seconds following rapid intravenous injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1 to 3 minutes, with optimum contrast occurring within 5 to 15 minutes.

12.3 Pharmacokinetics

In an in vitrohuman plasma study, iodixanol did not bind to protein. The volume of distribution in adults was 0.26 L/kg body weight, consistent with distribution to extracellular space.

In 40 healthy, young male volunteers receiving a single intravenous administration of iodixanol in doses of 0.3 gram Iodine/kg to 1.2 gram Iodine/kg body weight, the elimination half-life was 2.1 hr. (± 0.1). Renal clearance was 110 ± 14 mL/min, equivalent to glomerular filtration (108 mL/min). These values were independent of the dose administered.

Iodixanol does not undergo metabolism.

In adults, approximately 97% of the injected dose of iodixanol is excreted unchanged in urine within 24 hours, with less than 2% excreted in feces within five days post-injection.

Pediatric:Forty pediatric patients ≤12 years old, with renal function that is normal for their age, received multiple intra-arterial administrations of iodixanol in doses of 0.32 gram Iodine/kg to 3.2 gram Iodine/kg body weight. The elimination half-lives for these patients are shown in Table 5.

Dose adjustments to account for differences in elimination half-life in pediatric patients less than 6 months of age have not been studied.

TABLE 5

MEAN ELIMINATION HALF-LIFE* IN PEDIATRIC PATIENTS

Age Range Number of Patients Elimination half-life

(hr. ± SD)

Newborn to < 2 months 8 4.1 ± 1.4

2 to 6 months 8 2.8 ± 0.6

6 to 12 months 9 2.4 ± 0.4

1 to 2 years 5 2.3 ± 0.6

2 to 12 years 10 2.3 ± 0.5

Adults 40 2.1 ± 0.1

Renal Impairment:In patients with significantly impaired renal function, the total clearance of iodixanol is reduced and the half-life is increased. In a study of 16 adult patients who were scheduled for renal transplant, the mean creatinine clearance was 13.6 ± 4.7 mL/min). In these patients, plasma half-life was 23 hours (t _1/2for typical patients = 2.1 hours). Contrast enhancement time in kidneys increased from 6 hours to at least 24 hours. Dose adjustments in patients with renal impairment have not been studied. In patients with normal blood brain barriers and severe renal impairment, iodinated contrast agents have been associated with blood-brain barrier disruption and accumulation of contrast in the brain. Iodixanol has been shown to be dialyzable. In an in vitro hemodialysis study, after 4 hours of dialysis with a cellulose membrane, approximately 36% of iodixanol was removed from the plasma. After 4 hours of dialysis with polysulfone membranes, approximately 49% of iodixanol was removed.

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed with iodixanol to evaluate carcinogenic potential. Iodixanol was not genotoxic in a series of studies including the Ames test, the CHO/HGPRT assay, a chromosome aberration assay in CHO cells, and a mouse micronucleus assay.

Iodixanol did not impair the fertility of male or female rats when administered at doses up to 0.24 times the maximum recommended human dose.

14 Clinical Studies

Iodixanol was studied in 1,244 adult patients. Approximately one-half (590) of the iodixanol patients were 60 years of age or older; the mean age was 56 years (range 18 to 90). A total of patients, 806 (65%) were male. The racial distribution was: Caucasian-85%, Black-12%, Oriental <1%, and other or unknown-3%.

A total of 1,235 patients were evaluable for efficacy. Efficacy assessment was based on quality of the radiographic diagnostic visualization (i.e., either: excellent, good, poor, or none) and on the ability to make a diagnosis (i.e., either: confirmed a previous diagnosis, found normal, or diagnosed new findings).

14.1 Intra-arterial Administration Studies

Angiocardiography, cerebral arteriography, peripheral arteriography, and visceral arteriography were studied with either one or both concentrations of iodixanol injection (270 mg Iodine/mL or 320 mg Iodine/mL). In these intra-arterial studies, diagnostic visualization ratings were good or excellent in all the patients and a radiologic diagnosis was made in all of the patients. In additional intra-arterial studies, overall quality of diagnostic visualization was rated optimal in the majority of patients and a radiologic diagnosis was made in all (100%) of the patients. The number of patients studied in each indication is provided below.

Angiocardiography was evaluated in two randomized, double-blind clinical studies in 101 adult patients given iodixanol 320 mg Iodine/mL. Seven additional angiocardiography studies were performed in 217 adult patients given iodixanol 320 mg Iodine/mL. Visualization ratings were good or excellent in all the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Cerebral arteriography was evaluated in two randomized, double-blind clinical trials in 51 adult patients given iodixanol 320 mg Iodine/mL. Two additional cerebral arteriography studies were performed in 15 adult patients given iodixanol 270 mg Iodine/mL, 40 patients given iodixanol 320 mg Iodine/mL. Visualization ratings were good or excellent in all the patients a radiologic diagnosis was made in the majority of the patients. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Peripheral arteriography was evaluated in two randomized, double-blind clinical trials in 49 adult patients given iodixanol 320 mg Iodine/mL. Four additional peripheral arteriography studies were performed in 41 adult patients given iodixanol 270 mg Iodine/mL, 85 patients given iodixanol 320 mg Iodine/mL. Visualization ratings were good or excellent in 100% of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Visceral arteriography was evaluated in two randomized, double-blind clinical trials in 55 adult patients given iodixanol 320 mg Iodine/mL. Visualization ratings were good or excellent in all of the patients; a radiologic diagnosis was made in the majority of the patients. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Similar studies with digital subtraction angiography (DSA) were completed with comparable findings noted in cerebral arteriography, peripheral arteriography, and visceral arteriography. Studies have not been conducted to determine the lowest effective concentration of iodixanol.

14.2 Intravenous Administration Studies

Excretory urography, computed tomography (CT) of the head, CT of the body, peripheral venography, and coronary computed tomography angiography (CCTA) were studied with either one or both iodixanol injection concentrations (270 mg Iodine/mL or 320 mg Iodine/mL). In the non-CCTA intravenous studies, diagnostic visualization ratings were good or excellent in 96% to 100% of the patients and a radiologic diagnosis was made in all of the patients given iodixanol. In the CCTA studies results were computed in terms of sensitivity and specificity compared to a standard of reference. The number of patients studied in each indication is provided below.

Excretory urography was evaluated in one uncontrolled, unblinded clinical trial in 40 patients, 20 given iodixanol 270 mg Iodine/mL and 20 given iodixanol 320 mg Iodine/mL, and in two randomized, double-blind clinical trials in 50 adult patients given iodixanol 270 mg Iodine/mL, 50 patients given iodixanol 320 mg Iodine/mL. Visualization ratings were good or excellent in all of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

CT of the head was evaluated in two randomized, double-blind clinical trials in 49 adult patients given iodixanol 270 mg Iodine/mL, in 50 patients given iodixanol 320 mg Iodine/mL. CT of the body was evaluated in three randomized, double-blind clinical trials in 104 adult patients given iodixanol 270 mg Iodine/mL, and 109 patients given iodixanol 320 mg Iodine/mL. In both CT of the head and body, visualization ratings were good or excellent in all of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Peripheral venography was evaluated in two randomized, double-blind clinical studies in 46 adult patients given iodixanol 270 mg Iodine/mL. Visualization ratings were good or excellent in all of the patients given iodixanol; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active control. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Iodixanol 320 mg Iodine/mL for CCTA was evaluated in two prospective, multicenter clinical studies in a total of 1106 adult patients. The patient population consisted of stable outpatients with chest pain or other symptoms suggestive of coronary artery disease, and no known history of coronary disease. All the CCTAs were done using 64 detector row CT scanners. Most of the patients received beta-blocker medication for heart rate control and nitroglycerin for vasodilation. Patients with irregular cardiac rhythm or heart rate above 100 beats per minute were excluded. The mean patient age was 57 years in the first study and 59 years in the second study. Both studies had more men than women (59% male in the first study and 51% male in the second study), and more Caucasian patients (88% in the first study and 78% in the second study) than Black, Asian, or other patients. The BMI range was 17 to 50 with a mean of 31 in the first study and a BMI range of 15 to 71 with a mean of 30 in the second study.

In the first study, 230 patients (906 vessels) were evaluable for efficacy using the reference standard of invasive coronary angiography. Seventy-five vessels (8%, in 49 patients) were evaluated as positive for ≥50% stenosis. The CCTA images were randomized and read by three blinded, independent readers; the coronary angiography images were interpreted by an independent, blinded reader. Assuming independence between vessels, the vessel-level sensitivity (95% CI) for assessing ≥50% stenosis was 76% (63, 86) for reader 1, 89% (79, 95) for reader 2 and 77% (65, 86) for reader 3. The vessel-level specificity (95% CI) was 85% (81, 89) for reader 1, 84% (81, 87) for reader 2, and 89% (86, 91) for reader 3. The vessel-level sensitivity and specificity for assessing ≥70% stenosis were similar.

In a second study, 857 patients were evaluable for efficacy. Patients were followed up for 12 months after CCTA and the reference standard was a composite of pre-specified clinical outcomes (death, major adverse cardiac event, or coronary revascularization). Seventy-six patients (9%) experienced one or more of the pre-specified outcomes over 12 months of follow-up. The sensitivity (95% CI) and specificity (95% CI) of a positive CCTA finding (≥50% stenosis at the patient level) to predict one or more of the pre-specified clinical outcomes was 95% (87, 99) and 87% (84, 89), respectively.

16 How Supplied/storage And Handling

16.1 How Supplied

Iodixanol injection, USP is a ready-to-use sterile, pyrogen-free, preservative free, colorless to pale yellow solution available in two (2) strengths. It is supplied in the following configurations:

Iodixanol Injection, USP, 270 mg Iodine/mL:

Product Code Unit of Sale Each

381100 NDC 65219-381-10 Unit of 10 NDC 65219-381-03 100 mL single-dose polypropylene bottle

381150 NDC 65219-381-50 Unit of 10 NDC 65219-381-05 150 mL single-dose polypropylene bottle

Iodixanol Injection, USP, 320 mg Iodine/mL:

Product Code Unit of Sale Each

383105 NDC 65219-383-05 Unit of 10 NDC 65219-383-02 50 mL single-dose polypropylene bottle

383110 NDC 65219-383-10 Unit of 10 NDC 65219-383-04 100 mL single-dose polypropylene bottle

383150 NDC 65219-383-50 Unit of 10 NDC 65219-383-06 150 mL single-dose polypropylene bottle

383200 NDC 65219-383-70 Unit of 10 NDC 65219-383-08 200 mL single-dose polypropylene bottle

16.2 Storageand Handling

Protect iodixanol injection, USP from direct exposure to sunlight.

Store iodixanol injection, USP at controlled room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Iodixanol injection, USP may be stored in a contrast media warmer for up to one month at 37°C (98.6°F).

Do not freeze. Discard any product that is inadvertently frozen, as freezing may compromise the closure integrity of the immediate container.

DO NOT USE IF TAMPER-EVIDENT RING IS BROKEN OR MISSING.

17 Patient Counseling Information

Hypersensitivity Reactions

Advise the patient concerning the risk of hypersensitivity reactions that can occur both during and after iodixanol injection 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 iodixanol injection [see Warnings and Precautions (5.11)] .

Contrast-Induced Acute Kidney Injury

Advise the patient concerning appropriate hydration to decrease the risk of contrast-induced acute 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 iodixanol injection administration. Advise parents/caregivers about when to seek medical care for their child to monitor for thyroid dysfunction [see Warnings and Precautions (5.8)] .

Manufactured for:

FRESENIUS KABI USA, LLC

Lake Zurich, IL 60047

www.fresenius-kabi.com/us

Made in China

451700C 23UF04

Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, USP, 6 mg/mL

30 mg/5 mL (6 mg/mL)

Description

Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is a sterile aqueous suspension containing 3 mg per milliliter betamethasone, as betamethasone sodium phosphate, and 3 mg per milliliter betamethasone acetate. Inactive ingredients per mL: 7.1 mg dibasic sodium phosphate anhydrous; 3.4 mg monobasic sodium phosphate monohydrate; 0.1 mg edetate disodium; and 0.2 mg benzalkonium chloride as a preservative. The pH is adjusted to between 6.8 and 7.2.

The formula for betamethasone sodium phosphate is C ₂₂H ₂₈FNa ₂O ₈P and it has a molecular weight of 516.40. Chemically, it is 9-Fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 21-(disodium phosphate).

The formula for betamethasone acetate is C ₂₄H ₃₁FO ₆and it has a molecular weight of 434.50. Chemically, it is 9-Fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 21-acetate.

The chemical structures for betamethasone sodium phosphate and betamethasone acetate are as follows:
Structural Formula
Structural Formula

Betamethasone sodium phosphate is a white to practically white, odorless powder, and is hygroscopic. It is freely soluble in water and in methanol, but is practically insoluble in acetone and in chloroform.

Betamethasone acetate is a white to creamy white, odorless powder that sinters and resolidifies at about 165ºC, and remelts at about 200ºC to 220ºC with decomposition. It is practically insoluble in water, but freely soluble in acetone, and is soluble in alcohol and in chloroform.

Clinical Pharmacology

Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract.

Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their anti-inflammatory effects in disorders of many organ systems. A derivative of prednisolone, betamethasone has a 16β-methyl group that enhances the anti-inflammatory action of the molecule and reduces the sodium- and water-retaining properties of the fluorine atom bound at carbon 9.

Betamethasone sodium phosphate, a soluble ester, provides prompt activity, while betamethasone acetate is only slightly soluble and affords sustained activity.

Indications And Usage

When oral therapy is not feasible, the intramuscular useof Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is indicated as follows:

Allergic StatesControl of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions.

Dermatologic DiseasesBullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome).

Endocrine DisordersCongenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis.

Hydrocortisone or cortisone is the drug of choice in primary or secondary adrenocortical insufficiency. Synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance.

Gastrointestinal DiseasesTo tide the patient over a critical period of the disease in regional enteritis and ulcerative colitis.

Hematologic DisordersAcquired (autoimmune) hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, selected cases of secondary thrombocytopenia.

MiscellaneousTrichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used with appropriate antituberculous chemotherapy.

Neoplastic DiseasesFor palliative management of leukemias and lymphomas.

Nervous SystemAcute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor or craniotomy.

Ophthalmic DiseasesSympathetic ophthalmia, temporal arteritis, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids.

Renal DiseasesTo induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus.

Respiratory DiseasesBerylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis.

Rheumatic DisordersAs adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, polymyositis, and systemic lupus erythematosus.

The intra-articular or soft tissue administrationof Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is indicated as adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, synovitis of osteoarthritis.

The intralesional administrationof Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is indicated for alopecia areata; discoid lupus erythematosus; keloids; localized hypertrophic, infiltrated, inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus (neurodermatitis), and psoriatic plaques; necrobiosis lipoidica diabeticorum.

Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension may also be useful in cystic tumors of an aponeurosis or tendon (ganglia).

Contraindications

Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is contraindicated in patients who are hypersensitive to any components of this product (see DESCRIPTION ). Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura.

Warnings

Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension should not be administered intravenously.

Serious Neurologic Adverse Reactions with Epidural Administration

Serious neurologic events, some resulting in death, have been reported with epidural injection of corticosteroids. Specific events reported include, but are not limited to, spinal cord infarction, paraplegia, quadriplegia, cortical blindness, and stroke. These serious neurologic events have been reported with and without use of fluoroscopy. The safety and effectiveness of epidural administration of corticosteroids have not been established, and corticosteroids are not approved for this use.

General

Rare instances of anaphylactoid/anaphylactic reactions with a possibility of shock have occurred in patients receiving parenteral corticosteroid therapy (see ADVERSE REACTIONS). Use caution in patients who have a history of allergic reaction to corticosteroids.

In patients on corticosteroid therapy subjected to any unusual stress, hydrocortisone or cortisone is the drug of choice as a supplement during and after the event.

Cardio-Renal

Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.

Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

Endocrine

Corticosteroids can produce reversible hypothalamic pituitary adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment.

Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.

Infections

Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan, or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents. These infections may be mild to severe. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection.

Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see PRECAUTIONS, Drug Interactions, Amphotericin B Injection and Potassium-Depleting Agentssection).

Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococcus, Mycobacterium, Nocardia, Pneumocystis, and Toxoplasma. It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea.

Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Corticosteroids should not be used in cerebral malaria.

The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the response to such vaccines cannot be predicted.Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison’s disease.

Chickenpox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents should be considered.

Neurologic

Reports of severe medical events have been associated with the intrathecal route of administration (see ADVERSE REACTIONS, Gastrointestinal and Neurologic/Psychiatric sections).

Results from one multicenter, randomized, placebo-controlled study with methylprednisolone hemisuccinate, an intravenous corticosteroid, showed an increase in early mortality (at 2 weeks) and late mortality (at 6 months) in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of corticosteroids, including Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, should not be used for the treatment of traumatic brain injury.

Ophthalmic

Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Consider referral to an ophthalmologist for patients who develop ocular symptoms or use corticosteroid-containing products for more than 6 weeks. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should not be used in active ocular herpes simplex.

Precautions

General

This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial.

The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual.

Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.

Kaposi’s sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.

Cardio-Renal

As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency.

Endocrine

Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy. Therefore, in any situation of stress occurring during that period, naturally occurring glucocorticoids (hydrocortisone cortisone), which also have salt-retaining properties, rather than betamethasone, are the appropriate choices as replacement therapy in adrenocortical deficiency states.

Gastrointestinal

Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation.

Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent.

There is an enhanced effect of corticosteroids in patients with cirrhosis.

Intra-Articular and Soft Tissue Administration

Intra-articular injected corticosteroids may be systemically absorbed.

Appropriate examination of any joint fluid present is necessary to exclude a septic process.

A marked increase in pain accompanied by local swelling, further restriction of joint motion, fever, and malaise are suggestive of septic arthritis. If this complication occurs and the diagnosis of sepsis is confirmed, appropriate antimicrobial therapy should be instituted.

Injection of a steroid into an infected site is to be avoided. Local injection of a steroid into a previously injected joint is not usually recommended.

Corticosteroid injection into unstable joints is generally not recommended.

Intra-articular injection may result in damage to joint tissues (see ADVERSE REACTIONS, Musculoskeletal section).

Musculoskeletal

Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy.

Neuro-Psychiatric

Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect (see DOSAGE AND ADMINISTRATION).

An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders with neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy of neuromuscular blocking drugs (eg, pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

Information for Patients

Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection.

Persons who are on corticosteroids should be warned to avoid exposure to chickenpox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

Drug Interactions

Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression.

When corticosteroids are administered concomitantly with potassium-depleting agents (ie, amphotericin B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure.

Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance.

Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.

Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect.

Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required.

Serum concentrations of isoniazid may be decreased.

Cholestyramine may increase the clearance of corticosteroids.

Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use.

Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia.

Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect.

Drugs which induce hepatic microsomal drug-metabolizing enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased.

Corticosteroids (including betamethasone) are metabolized by CYP3A4.

Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects.

Coadministration with other strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir, cobicistat-containing products) may lead to increased exposures of corticosteroids and therefore the potential for increased risk of systemic corticosteroid side effects.

Consider the benefit of coadministration versus the potential risk of systemic corticosteroid effects, in which case patients should be monitored for systemic corticosteroid side effects.

Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids.

Corticosteroids may suppress reactions to skin tests.

Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Route administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccinationsection).

Carcinogenesis, Mutagenesis, Impairment of Fertility

No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis.

Steroids may increase or decrease motility and number of spermatozoa in some patients.

Pregnancy

Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

Nursing Mothers

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when corticosteroids are administered to a nursing woman.

Pediatric Use

The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids, which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (> 2 years of age), and aggressive lymphomas and leukemias (> 1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations.

The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose.

Geriatric Use

No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and young patients, but greater sensitivity of some older individuals cannot be ruled out.

Adverse Reactions

(uled alphabetically, under each subsection)

Allergic Reactions

Anaphylactoid reaction, anaphylaxis, angioedema.

Cardiovascular

Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.

Dermatologic

Acne, allergic dermatitis, cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.

Endocrine

Decreased carbohydrate and glucose tolerance, development of cushingoid state, glucosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients.

Fluid and Electrolyte Disturbances

Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention.

Gastrointestinal

Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis.

Metabolic

Negative nitrogen balance due to protein catabolism.

Musculoskeletal

Aseptic necrosis of femoral and humeral heads, calcinosis (following intra-articular or intralesional use), Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures.

Neurologic/Psychiatric

Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration (see WARNINGS, Neurologicsection).

Ophthalmic

Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections, vision blurred.

Other

Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, malaise, moon face, weight gain.

Overdosage

Treatment of acute overdose is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced.

Dosage And Administration

Benzyl alcohol as a preservative has been associated with a fatal “Gasping Syndrome” in premature infants and infants of low birth weight. Solutions used for further dilution of this product should be preservative-free when used in the neonate, especially the premature infant. The initial dosage of parenterally administered Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension may vary from 0.25 to 9 mg per day depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administrations in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.

It Should Be Emphasized That Dosage Requirements Are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient.After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

In the treatment of acute exacerbations of multiple sclerosis, daily doses of 30 mg of betamethasone for a week followed by 12 mg every other day for 1 month are recommended (see PRECAUTIONS, Neuro-psychiatricsection).

In pediatric patients, the initial dose of betamethasone may vary depending on the specific disease entity being treated. The range of initial doses is 0.02 to 0.3 mg/kg/day in three or four divided doses (0.6 to 9 mg/m ²bsa/day).

For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids:

Cortisone, 25 Triamcinolone, 4

Hydrocortisone, 20 Paramethasone, 2

Prednisolone, 5 Betamethasone, 0.75

Prednisone, 5 Dexamethasone, 0.75

Methylprednisolone, 4

These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered.

If coadministration of a local anesthetic is desired, Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension may be mixed with 1% or 2% lidocaine hydrochloride, using the formulations which do not contain parabens. Similar local anesthetics may also be used. Diluents containing methylparaben, propylparaben, phenol, etc., should be avoided, since these compounds may cause flocculation of the steroid. The required dose of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is first withdrawn from the vial into the syringe. The local anesthetic is then drawn in, and the syringe shaken briefly. Do not inject local anesthetics into the vial of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension.

Bursitis, Tenosynovitis, Peritendinitis

In acute subdeltoid, subacromial, olecranon, and prepatellar bursitis, one intrabursal injection of 1 mL Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension can relieve pain and restore full range of movement. Several intrabursal injections of corticosteroids are usually required in recurrent acute bursitis and in acute exacerbations of chronic bursitis. Partial relief of pain and some increase in mobility can be expected in both conditions after one or two injections. Chronic bursitis may be treated with reduced dosage once the acute condition is controlled. In tenosynovitis and tendinitis, three or four local injections at intervals of 1 to 2 weeks between injections are given in most cases. Injections should be made into the affected tendon sheaths rather than into the tendons themselves. In ganglions of joint capsules and tendon sheaths, injection of 0.5 mL directly into the ganglion cysts has produced marked reduction in the size of the lesions.

Rheumatoid Arthritis and Osteoarthritis

Following intra-articular administration of 0.5 to 2 mL of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, relief of pain, soreness, and stiffness may be experienced. Duration of relief varies widely in both diseases. Intra-articular Injection of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is well tolerated in joints and periarticular tissues. There is virtually no pain on injection, and the “secondary flare” that sometimes occurs a few hours after intra-articular injection of corticosteroids has not been reported with Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension. Using sterile technique, a 20- to 24-gauge needle on an empty syringe is inserted into the synovial cavity and a few drops of synovial fluid are withdrawn to confirm that the needle is in the joint. The aspirating syringe is replaced by a syringe containing Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension and injection is then made into the joint.

Recommended Doses for Intra-articular Injection

Size of Joint Location Dose (mL)

Very Large Hip 1 - 2

Large Knee, ankle, shoulder 1

Medium Elbow, wrist 0.5 - 1

Small (metacarpophalangeal, interphalangeal) (sternoclavicular) Hand, chest 0.25 to 0.5

A portion of the administered dose of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is absorbed systemically following intra-articular injection. In patients being treated concomitantly with oral or parenteral corticosteroids, especially those receiving large doses, the systemic absorption of the drug should be considered in determining intra-articular dosage.

Dermatologic Conditions

In intralesional treatment, 0.2 mL/cm ²of Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension is injected intradermally (not subcutaneously) using a tuberculin syringe with a 25-gauge, 1/2-inch needle. Care should be taken to deposit a uniform depot of medication intradermally. A total of no more than 1 mL at weekly intervals is recommended.

Disorders of the Foot

A tuberculin syringe with a 25-gauge, 3/4-inch needle is suitable for most injections into the foot. The following doses are recommended at intervals of 3 days to a week.

Diagnosis Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension Dose (mL)

Bursitis under heloma durum or heloma molle
0.25 to 0.5

under calcaneal spur 0.5

over hallux rigidus or digiti quinti varus 0.5

Tenosynovitis, periostitis of cuboid 0.5

Acute gouty arthritis 0.5 to 1

How Supplied

NDC 0517-0720-01:

Betamethasone Sodium Phosphate and Betamethasone Acetate Injectable Suspension, 5 mL multiple dose vial; box of one. Inactive ingredients per mL: 7.1 mg dibasic sodium phosphate anhydrous; 3.4 mg monobasic sodium phosphate monohydrate; 0.1 mg edetate disodium; and 0.2 mg benzalkonium chloride as preservative.

SHAKE WELL BEFORE USING.

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from light.

Rx only

AMERICAN REGENT, INC. SHIRLEY, NY 11967

Revised July 2018

Lidocaine HCl Injection, USP

For Infiltration and Nerve Block Including Caudal and Epidural Use.

Preservative-Free

Rx only

Description

Lidocaine hydrochloride injection, USP is sterile, nonpyrogenic, aqueous solution that contains a local anesthetic agent and is administered parenterally by injection. See INDICATIONS AND USAGE section for specific uses. Lidocaine hydrochloride injection, USP contains lidocaine hydrochloride, which is chemically designated as acetamide, 2-(diethylamino)-N-(2,6-dimethylphenyl)-, monohydrochloride and has the molecular weight 270.8. Lidocaine hydrochloride (C ₁₄H ₂₂N ₂O • HCl) has the following structural formula:

Lidocaine hydrochloride injection, USP is a sterile, nonpyrogenic, isotonic solution containing sodium chloride. The pH of the solution is adjusted to approximately 6.5 (5.0 to 7.0) with sodium hydroxide and/or hydrochloric acid.

Clinical Pharmacology

Mechanism of Action

Lidocaine hydrochloride stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby effecting local anesthetic action.

Hemodynamics

Excessive blood levels may cause changes in cardiac output, total peripheral resistance, and mean arterial pressure. With central neural blockade these changes may be attributable to block of autonomic fibers, a direct depressant effect of the local anesthetic agent on various components of the cardiovascular system, and/or the beta-adrenergic receptor stimulating action of epinephrine when present. The net effect is normally a modest hypotension when the recommended dosages are not exceeded.

Pharmacokinetics and Metabolism

Information derived from diverse formulations, concentrations and usages reveals that lidocaine hydrochloride is completely absorbed following parenteral administration, its rate of absorption depending, for example, upon various factors such as the site of administration and the presence or absence of a vasoconstrictor agent. Except for intravascular administration, the highest blood levels are obtained following intercostal nerve block and the lowest after subcutaneous administration. The plasma binding of lidocaine hydrochloride is dependent on drug concentration, and the fraction bound decreases with increasing concentration. At concentrations of 1 to 4 mcg of free base per mL 60 to 80 percent of lidocaine hydrochloride is protein bound. Binding is also dependent on the plasma concentration of the alpha-1-acid glycoprotein. Lidocaine hydrochloride crosses the blood-brain and placental barriers, presumably by passive diffusion. Lidocaine hydrochloride is metabolized rapidly by the liver, and metabolites and unchanged drug are excreted by the kidneys. Biotransformation includes oxidative N-dealkylation, ring hydroxylation, cleavage of the amide linkage, and conjugation. N-dealkylation, a major pathway of biotransformation, yields the metabolites monoethylglycinexylidide and glycinexylidide. The pharmacological/toxicological actions of these metabolites are similar to, but less potent than, those of lidocaine hydrochloride. Approximately 90% of lidocaine hydrochloride administered is excreted in the form of various metabolites, and less than 10% is excreted unchanged. The primary metabolite in urine is a conjugate of 4-hydroxy-2,6-dimethylaniline. The elimination half-life of lidocaine hydrochloride following an intravenous bolus injection is typically 1.5 to 2 hours. Because of the rapid rate at which lidocaine hydrochloride is metabolized, any condition that affects liver function may alter lidocaine hydrochloride kinetics. The half-life may be prolonged two-fold or more in patients with liver dysfunction. Renal dysfunction does not affect lidocaine hydrochloride kinetics but may increase the accumulation of metabolites. Factors such as acidosis and the use of CNS stimulants and depressants affect the CNS levels of lidocaine hydrochloride required to produce overt systemic effects. Objective adverse manifestations become increasingly apparent with increasing venous plasma levels above 6 mcg free base per mL. In the rhesus monkey arterial blood levels of 18 to 21 mcg/mL have been shown to be threshold for convulsive activity.

Indications And Usage

Lidocaine hydrochloride injection is indicated for production of local or regional anesthesia by infiltration techniques such as percutaneous injection and intravenous regional anesthesia by peripheral nerve block techniques such as brachial plexus and intercostal and by central neural techniques such as lumbar and caudal epidural blocks, when the accepted procedures for these techniques as described in standard textbooks are observed.

Contraindications

Lidocaine hydrochloride is contraindicated in patients with a known history of hypersensitivity to local anesthetics of the amide type.

Warnings

LIDOCAINE HYDROCHLORIDE INJECTION FOR INFILTRATION AND NERVE BLOCK SHOULD BE EMPLOYED ONLY BY CLINICIANS WHO ARE WELL VERSED IN DIAGNOSIS AND MANAGEMENT OF DOSE-RELATED TOXICITY AND OTHER ACUTE EMERGENCIES THAT MIGHT ARISE FROM THE BLOCK TO BE EMPLOYED AND THEN ONLY AFTER ENSURING THE IMMEDIATEAVAILABILITY OF OXYGEN, OTHER RESUSCITATIVE DRUGS, CARDIOPULMONARY EQUIPMENT AND THE PERSONNEL NEEDED FOR PROPER MANAGEMENT OF TOXIC REACTIONS AND RELATED EMERGENCIES (see also ADVERSE REACTIONS and PRECAUTIONS ). DELAY IN PROPER MANAGEMENT OF DOSE-RELATED TOXICITY, UNDERVENTILATION FROM ANY CAUSE AND/OR ALTERED SENSITIVITY MAY LEAD TO THE DEVELOPMENT OF ACIDOSIS, CARDIAC ARREST AND, POSSIBLY, DEATH. Methemoglobinemia Cases of methemoglobinemia have been reported in association with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing clinical manifestations of the condition. If local anesthetics must be used in these patients, close monitoring for symptoms and signs of methemoglobinemia is recommended. Signs of methemoglobinemia may occur immediately or may be delayed some hours after exposure, and are characterized by a cyanotic skin discoloration and/or abnormal coloration of the blood. Methemoglobin levels may continue to rise; therefore, immediate treatment is required to avert more serious central nervous system and cardiovascular adverse effects, including seizures, coma, arrhythmias, and death. Discontinue lidocaine hydrochloride and any other oxidizing agents. Depending on the severity of the signs and symptoms, patients may respond to supportive care, i.e., oxygen therapy, hydration. A more severe clinical presentation may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. Intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures is an unapproved use, and there have been post-marketing reports of chondrolysis in patients receiving such infusions. The majority of reported cases of chondrolysis have involved the shoulder joint; cases of gleno-humeral chondrolysis have been described in pediatric and adult patients following intra-articular infusions of local anesthetics with and without epinephrine for periods of 48 to 72 hours. There is insufficient information to determine whether shorter infusion periods are not associated with these findings. The time of onset of symptoms, such as joint pain, stiffness and loss of motion can be variable, but may begin as early as the 2 ^ndmonth after surgery. Currently, there is no effective treatment for chondrolysis; patients who experienced chondrolysis have required additional diagnostic and therapeutic procedures and some required arthroplasty or shoulder replacement. To avoid intravascular injection, aspiration should be performed before the local anesthetic solution is injected. The needle must be repositioned until no return of blood can be elicited by aspiration. Note, however, that the absence of blood in the syringe does not guarantee that intravascular injection has been avoided. Anaphylactic reactions may occur following administration of lidocaine hydrochloride (see ADVERSE REACTIONS ). In the case of severe reaction, discontinue the use of the drug.

Precautions

General

The safety and effectiveness of lidocaine hydrochloride depend on proper dosage, correct technique, adequate precautions, and readiness for emergencies. Standard textbooks should be consulted for specific techniques and precautions for various regional anesthetic procedures. Resuscitative equipment, oxygen, and other resuscitative drugs should be available for immediate use (see WARNINGS and ADVERSE REACTIONS ). The lowest dosage that results in effective anesthesia should be used to avoid high plasma levels and serious adverse effects. Syringe aspirations should also be performed before and during each supplemental injection when using indwelling catheter techniques. During the administration of epidural anesthesia, it is recommended that a test dose be administered initially and that the patient be monitored for central nervous system toxicity and cardiovascular toxicity, as well as for signs of unintended intrathecal administration, before proceeding. When clinical conditions permit, consideration should be given to employing local anesthetic solutions that contain epinephrine for the test dose because circulatory changes compatible with epinephrine may also serve as a warning sign of unintended intravascular injection. An intravascular injection is still possible even if aspirations for blood are negative. Repeated doses of lidocaine hydrochloride may cause significant increases in blood levels with each repeated dose because of slow accumulation of the drug or its metabolites. Tolerance to elevated blood levels varies with the status of the patient. Debilitated, elderly patients, acutely ill patients, and children should be given reduced doses commensurate with their age and physical condition. Lidocaine hydrochloride should also be used with caution in patients with severe shock or heart block. Lumbar and caudal epidural anesthesia should be used with extreme caution in persons with the following conditions: existing neurological disease, spinal deformities, septicemia, and severe hypertension. Local anesthetic solutions containing a vasoconstrictor should be used cautiously and in carefully circumscribed quantities in areas of the body supplied by end arteries or having otherwise compromised blood supply. Patients with peripheral vascular disease and those with hypertensive vascular disease may exhibit exaggerated vasoconstrictor response. Ischemic injury or necrosis may result. Preparations containing a vasoconstrictor should be used with caution in patients during or following the administration of potent general anesthetic agents, since cardiac arrhythmias may occur under such conditions. Careful and constant monitoring of cardiovascular and respiratory (adequacy of ventilation) vital signs and the patient’s state of consciousness should be accomplished after each local anesthetic injection. It should be kept in mind at such times that restlessness, anxiety, tinnitus, dizziness, blurred vision, tremors, depression or drowsiness may be early warning signs of central nervous system toxicity. Since amide-type local anesthetics are metabolized by the liver, lidocaine hydrochloride injection should be used with caution in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations. Lidocaine hydrochloride injection should also be used with caution in patients with impaired cardiovascular function since they may be less able to compensate for functional changes associated with the prolongation of A-V conduction produced by these drugs. Many drugs used during the conduct of anesthesia are considered potential triggering agents for familial malignant hyperthermia. Since it is not known whether amide-type local anesthetics may trigger this reaction and since the need for supplemental general anesthesia cannot be predicted in advance, it is suggested that a standard protocol for the management of malignant hyperthermia should be available. Early unexplained signs of tachycardia, tachypnea, labile blood pressure and metabolic acidosis may precede temperature elevation. Successful outcome is dependent on early diagnosis, prompt discontinuance of the suspect triggering agent(s) and institution of treatment, including oxygen therapy, indicated supportive measures and dantrolene (consult dantrolene sodium intravenous package insert before using). Proper tourniquet technique, as described in publications and standard textbooks, is essential in the performance of intravenous regional anesthesia. Solutions containing epinephrine or other vasoconstrictors should not be used for this technique. Lidocaine hydrochloride should be used with caution in persons with known drug sensitivities. Patients allergic to para-aminobenzoic acid derivatives (procaine, tetracaine, benzocaine, etc.) have not shown cross-sensitivity to lidocaine hydrochloride.

Use in the Head and Neck Area

Small doses of local anesthetics injected into the head and neck area, including retrobulbar, dental and stellate ganglion blocks, may produce adverse reactions similar to systemic toxicity seen with unintentional intravascular injections of larger doses. Confusion, convulsions, respiratory depression and/or respiratory arrest, and cardiovascular stimulation or depression have been reported. These reactions may be due to intra-arterial injection of the local anesthetic with retrograde flow to the cerebral circulation. Patients receiving these blocks should have their circulation and respiration monitored and be constantly observed. Resuscitative equipment and personnel for treating adverse reactions should be immediately available. Dosage recommendations should not be exceeded (see DOSAGE AND ADMINISTRATION ).

Information for Patients

When appropriate, patients should be informed in advance that they may experience temporary loss of sensation and motor activity, usually in the lower half of the body, following proper administration of epidural anesthesia. Inform patients that use of local anesthetics may cause methemoglobinemia, a serious condition that must be treated promptly. Advise patients or caregivers to seek immediate medical attention if they or someone in their care experience the following signs or symptoms: pale, gray, or blue colored skin (cyanosis); headache; rapid heart rate; shortness of breath; lightheadedness; or fatigue.

Clinically Significant Drug Interactions

The administration of local anesthetic solutions containing epinephrine or norepinephrine to patients receiving monoamine oxidase inhibitors or tricyclic antidepressants may produce severe, prolonged hypertension. Phenothiazines and butyrophenones may reduce or reverse the pressor effect of epinephrine. Concurrent use of these agents should generally be avoided. In situations when concurrent therapy is necessary, careful patient monitoring is essential. Concurrent administration of vasopressor drugs (for the treatment of hypotension related to obstetric blocks) and ergot-type oxytocic drugs may cause severe, persistent hypertension or cerebrovascular accidents.

Drug/Laboratory Test Interactions

The intramuscular injection of lidocaine hydrochloride may result in an increase in creatine phosphokinase levels. Thus, the use of this enzyme determination, without isoenzyme separation, as a diagnostic test for the presence of acute myocardial infarction may be compromised by the intramuscular injection of lidocaine hydrochloride. Patients who are administered local anesthetics are at increased risk of developing methemoglobinemia when concurrently exposed to the following drugs, which could include other local anesthetics:

Examples of Drugs Associated with Methemoglobinemia:

Class Examples

Nitrates/Nitrites nitric oxide, nitroglycerin, nitroprusside, nitrous oxide

Local anesthetics articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine

Antineoplastic agents cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase

Antibiotics dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides

Antimalarials chloroquine, primaquine

Anticonvulsants Phenobarbital, phenytoin, sodium valproate

Other drugs acetaminophen, metoclopramide, quinine, sulfasalazine

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies of lidocaine hydrochloride in animals to evaluate the carcinogenic and mutagenic potential or the effect on fertility have not been conducted.

Pregnancy

Teratogenic Effects

Reproduction studies have been performed in rats at doses up to 6.6 times the human dose and have revealed no evidence of harm to the fetus caused by lidocaine hydrochloride. There are, however, no adequate and well-controlled studies in pregnant women. Animal reproduction studies are not always predictive of human response. General consideration should be given to this fact before administering lidocaine hydrochloride to women of childbearing potential, especially during early pregnancy when maximum organogenesis takes place.

Labor and Delivery

Local anesthetics rapidly cross the placenta and when used for epidural, paracervical, pudendal or caudal block anesthesia, can cause varying degrees of maternal, fetal and neonatal toxicity (see CLINICAL PHARMACOLOGY , Pharmacokinetics and Metabolism ). The potential for toxicity depends upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function. Maternal hypotension has resulted from regional anesthesia. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient’s legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Epidural, spinal, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. In one study, paracervical block anesthesia was associated with a decrease in the mean duration of first stage labor and facilitation of cervical dilation. However, spinal and epidural anesthesia have also been reported to prolong the second stage of labor by removing the parturient’s reflex urge to bear down or by interfering with motor function. The use of obstetrical anesthesia may increase the need for forceps assistance. The use of some local anesthetic drug products during labor and delivery may be followed by diminished muscle strength and tone for the first day or two of life. The long-term significance of these observations is unknown. Fetal bradycardia may occur in 20 to 30 percent of patients receiving paracervical nerve block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. Fetal heart rate should always be monitored during paracervical anesthesia. The physician should weigh the possible advantages against risks when considering a paracervical block in prematurity, toxemia of pregnancy, and fetal distress. Careful adherence to recommended dosage is of the utmost importance in obstetrical paracervical block. Failure to achieve adequate analgesia with recommended doses should arouse suspicion of intravascular or fetal intracranial injection. Cases compatible with unintended fetal intracranial injection of local anesthetic solution have been reported following intended paracervical or pudendal block or both. Babies so affected present with unexplained neonatal depression at birth, which correlates with high local anesthetic serum levels, and often manifest seizures within six hours. Prompt use of supportive measures combined with forced urinary excretion of the local anesthetic has been used successfully to manage this complication. Case reports of maternal convulsions and cardiovascular collapse following use of some local anesthetics for paracervical block in early pregnancy (as anesthesia for elective abortion) suggest that systemic absorption under these circumstances may be rapid. The recommended maximum dose of each drug should not be exceeded. Injection should be made slowly and with frequent aspiration. Allow a 5-minute interval between sides.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when lidocaine hydrochloride is administered to a nursing woman.

Pediatric Use

Dosages in children should be reduced, commensurate with age, body weight and physical condition, see DOSAGE AND ADMINISTRATION .

Adverse Reactions

Systemic

Adverse experiences following the administration of lidocaine hydrochloride are similar in nature to those observed with other amide local anesthetic agents. These adverse experiences are, in general, dose-related and may result from high plasma levels caused by excessive dosage, rapid absorption or inadvertent intravascular injection, or may result from a hypersensitivity, idiosyncrasy or diminished tolerance on the part of the patient. Serious adverse experiences are generally systemic in nature. The following types are those most commonly reported:

CNS manifestations are excitatory and/or depressant and may be characterized by lightheadedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, respiratory depression and arrest. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness and respiratory arrest.

Drowsiness following the administration of lidocaine hydrochloride is usually an early sign of a high blood level of the drug and may occur as a consequence of rapid absorption.

Cardiovascular manifestations are usually depressant and are characterized by bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest.

Allergic reactions are characterized by cutaneous lesions, urticaria, edema or anaphylactoid reactions. Allergic reactions may occur as a result of sensitivity to local anesthetic agents. Allergic reactions, including anaphylactic reactions, may occur as a result of sensitivity to lidocaine, but are infrequent. If allergic reactions do occur, they should be managed by conventional means. The detection of sensitivity by skin testing is of doubtful value. There have been no reports of cross sensitivity between lidocaine hydrochloride and procainamide or between lidocaine hydrochloride and quinidine.

The incidences of adverse reactions associated with the use of local anesthetics may be related to the total dose of local anesthetic administered and are also dependent upon the particular drug used, the route of administration and the physical status of the patient. In a prospective review of 10,440 patients who received lidocaine hydrochloride for spinal anesthesia, the incidences of adverse reactions were reported to be about 3 percent each for positional headaches, hypotension and backache; 2 percent for shivering; and less than 1 percent each for peripheral nerve symptoms, nausea, respiratory inadequacy and double vision. Many of these observations may be related to local anesthetic techniques, with or without a contribution from the local anesthetic. In the practice of caudal or lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter may occur. Subsequent adverse effects may depend partially on the amount of drug administered subdurally. These may include spinal block of varying magnitude (including total spinal block), hypotension secondary to spinal block, loss of bladder and bowel control, and loss of perineal sensation and sexual function. Persistent motor, sensory and/or autonomic (sphincter control) deficit of some lower spinal segments with slow recovery (several months) or incomplete recovery have been reported in rare instances when caudal or lumbar epidural block has been attempted. Backache and headache have also been noted following use of these anesthetic procedures. There have been reported cases of permanent injury to extraocular muscles requiring surgical repair following retrobulbar administration.

Methemoglobinemia.

Overdosage

Acute emergencies from local anesthetics are generally related to high plasma levels encountered during therapeutic use of local anesthetics or to unintended subarachnoid injection of local anesthetic solution (see ADVERSE REACTIONS , WARNINGS , and PRECAUTIONS ).

Management of Local Anesthetic Emergencies

The first consideration is prevention, best accomplished by careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic injection. At the first sign of change, oxygen should be administered. The first step in the management of convulsions, as well as underventilation or apnea due to unintended subarachnoid injection of drug solution, consists of immediate attention to the maintenance of a patent airway and assisted or controlled ventilation with oxygen and a delivery system capable of permitting immediate positive airway pressure by mask. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated, keeping in mind that drugs used to treat convulsions sometimes depress the circulation when administered intravenously. Should convulsions persist despite adequate respiratory support, and if the status of the circulation permits, small increments of an ultra-short acting barbiturate (such as thiopental or thiamylal) or a benzodiazepine (such as diazepam) may be administered intravenously. The clinician should be familiar, prior to the use of local anesthetics, with these anticonvulsant drugs. Supportive treatment of circulatory depression may require administration of intravenous fluids and, when appropriate, a vasopressor as directed by the clinical situation (e.g., ephedrine). If not treated immediately, both convulsions and cardiovascular depression can result in hypoxia, acidosis, bradycardia, arrhythmias and cardiac arrest. Underventilation or apnea due to unintentional subarachnoid injection of local anesthetic solution may produce these same signs and also lead to cardiac arrest if ventilatory support is not instituted. If cardiac arrest should occur, standard cardiopulmonary resuscitative measures should be instituted. Endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated, after initial administration of oxygen by mask, if difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated. Dialysis is of negligible value in the treatment of acute overdosage with lidocaine hydrochloride. The oral LD ₅₀of lidocaine hydrochloride in non-fasted female rats is 459 (346 to 773) mg/kg (as the salt) and 214 (159 to 324) mg/kg (as the salt) in fasted female rats.

Dosage And Administration

Table 1 (Recommended Dosages) summarizes the recommended volumes and concentrations of lidocaine hydrochloride injection for various types of anesthetic procedures. The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions. When larger volumes are required, only solutions containing epinephrine should be used except in those cases where vasopressor drugs may be contraindicated. There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. Lidocaine hydrochloride injection is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION ). These recommended doses serve only as a guide to the amount of anesthetic required for most routine procedures. The actual volumes and concentrations to be used depend on a number of factors such as type and extent of surgical procedure, depth of anesthesia and degree of muscular relaxation required, duration of anesthesia required, and the physical condition of the patient. In all cases the lowest concentration and smallest dose that will produce the desired result should be given. Dosages should be reduced for children and for the elderly and debilitated patients and patients with cardiac and/or liver disease. The onset of anesthesia, the duration of anesthesia and the degree of muscular relaxation are proportional to the volume and concentration (i.e., total dose) of local anesthetic used. Thus, an increase in volume and concentration of lidocaine hydrochloride injection will decrease the onset of anesthesia, prolong the duration of anesthesia, provide a greater degree of muscular relaxation and increase the segmental spread of anesthesia. However, increasing the volume and concentration of lidocaine hydrochloride injection may result in a more profound fall in blood pressure when used in epidural anesthesia. Although the incidence of side effects with lidocaine hydrochloride is quite low, caution should be exercised when employing large volumes and concentrations, since the incidence of side effects is directly proportional to the total dose of local anesthetic agent injected.

Epidural Anesthesia

For epidural anesthesia the following dosage form of lidocaine hydrochloride injection is recommended: 1% without epinephrine 30 mL single dose vials Although this solution is intended specifically for epidural anesthesia, it may also be used for infiltration and peripheral nerve block, provided it is employed as a single dose unit. This solution contains no bacteriostatic agent. In epidural anesthesia, the dosage varies with the number of dermatomes to be anesthetized (generally 2 to 3 mL of the indicated concentration per dermatome).

Caudal and Lumbar Epidural Block

As a precaution against the adverse experience sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2 to 3 mL of 1.5% lidocaine hydrochloride should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block. The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter. Epinephrine, if contained in the test dose (10 to 15 mcg have been suggested), may serve as a warning of unintentional intravascular injection. If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient. The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds. Patients on beta blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure. Adequate time should be allowed for onset of anesthesia after administration of each test dose. The rapid injection of a large volume of lidocaine hydrochloride injection through the catheter should be avoided, and, when feasible, fractional doses should be administered. In the event of the known injection of a large volume of local anesthetic solution into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.

Maximum Recommended Dosages

Adults

For normal healthy adults, the maximum individual dose should not exceed 4.5 mg/kg (2 mg/lb) of body weight, and in general it is recom mended that the max i m um t otal dose does not exceed 300 mg. For continuous epidural or caudal anesthesia, the maximum recommended dosage should not be administered at intervals of less than 90 minutes. When continuous lumbar or caudal epidural anesthesia is used for non-obstetrical procedures, more drug may be administered if required to produce adequate anesthesia. The maximum recommended dose per 90 minute period of lidocaine hydrochloride for paracervical block in obstetrical patients and non-obstetrical patients is 200 mg total. One half of the total dose is usually administered to each side. Inject slowly, five minutes between sides (see also discussion of paracervical block in PRECAUTIONS ). For intravenous regional anesthesia, the dose administered should not exceed 4 mg/kg in adults.

Children

It is difficult to recommend a maximum dose of any drug for children, since this varies as a function of age and weight. For children over 3 years of age who have a normal lean body mass and normal body development, the maximum dose is determined by the child’s age and weight. For example, in a child of 5 years weighing 50 lbs the dose of lidocaine hydrochloride should not exceed 75 to 100 mg (1.5 to 2 mg/lb). The use of even more dilute solutions (i.e., 0.25 to 0.5%) and total dosages not to exceed 3 mg/kg (1.4 mg/lb) are recommended for induction of intravenous regional anesthesia in children. In order to guard against systemic toxicity, the lowest effective concentration and lowest effective dose should be used at all times. In some cases it will be necessary to dilute available concentrations with 0.9% sodium chloride injection in order to obtain the required final concentration. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. Do not use if solution is discolored or contains a precipitate.

Table 1: Recommended Dosages

Procedure Lidocaine Hydrochloride Injection (without epinephrine)

Conc (%) Vol (mL) Total Dose (mg)

*Dose determined by number of dermatomes to be anesthetized (2 to 3 mL/dermatome).

Infiltration

Percutaneous 0.5 or 1 1 to 60 5 to 300

Intravenous regional 0.5 10 to 60 50 to 300

Peripheral Nerve Blocks, e.g.,

Brachial 1.5 15 to 20 225 to 300

Dental 2 1 to 5 20 to 100

Intercostal 1 3 30

Paravertebral 1 3 to 5 30 to 50

Pudendal (each side) 1 10 100

Paracervical

Obstetrical analgesia (each side) 1 10 100

Sympathetic Nerve Blocks, e.g.,

Cervical (stellate ganglion) 1 5 50

Lumbar 1 5 to 10 50 to 100

Central Neural Blocks

Epidural*

Thoracic 1 20 to 30 200 to 300

Lumbar

Analgesia 1 25 to 30 250 to 300

Anesthesia 1.5 15 to 20 225 to 300

2 10 to 15 200 to 300

Caudal

Obstetrical analgesia 1 20 to 30 200 to 300

Surgical anesthesia 1.5 15 to 20 225 to 300

THE ABOVE SUGGESTED CONCENTRATIONS AND VOLUMES SERVE ONLY AS A GUIDE. OTHER VOLUMES AND CONCENTRATIONS MAY BE USED PROVIDED THE TOTAL MAXIMUM RECOMMENDED DOSE IS NOT EXCEEDED.

Sterilization, Storage And Technical Procedures

Disinfecting agents containing heavy metals, which cause release of respective ions (mercury, zinc, copper, etc.) should not be used for skin or mucous membrane disinfection as they have been related to incidents of swelling and edema.

How Supplied

Lidocaine Hydrochloride Injection, USP is supplied as follows: Lidocaine Hydrochloride Injection USP, 1% (10 mg/mL) 5 mL Single Dose Vials             NDC 55150-162-05 Sterile, Nonpyrogenic Discard unused portion Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] The vial stopper is not made with natural rubber latex. Distributed by: AuroMedics Pharma LLC

279 Princeton-Hightstown Rd. E. Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited

Hyderabad - 500038 India Revised: February 2020

Povidine Iodine Swab

Otc - Active Ingredient Section

Active Ingredient                                                  Purpose

Povidone Iodine 10% w/v (9.85% w/w/)               Antiseptic

Purpose:

Purpose:

First aid antiseptic to help prevent skin infection in minor cuts, scrapes and burns.

For preparation of the skin prior to surgery.

Helps reduce bacteria that can potentially cause skin infections.

Warnings:

Section Text

FOR EXTERNAL USE ONLY

Do Not Use:

As a first aid antiseptic for more than 1 week.

In the eyes.

Over large areas of the body.

Ask A Doctor Before Use If You Have:

Deep puncture wounds

Animal bites

Serious burns

Stop Use:

If irritation and redness develop

If condition persists for more than 72 hours, consult a physician.

Keep Out Of Reach Of Children

Keep out of reach of children.If swallowed, get medical help or contact a Poison Control Center.

Directions Povidone Iodine:

Tear at notch, remove applicator, use only once.

As a first aid antiseptic

clean affected area

apply 1 to 3 times daily

may be covered with a sterile bandage, if bandaged let dry.

For preoperative patient skin preparation

clean area

apply to operative site prior to surgery using the applicator

Other Information:

Store at room temperature.

Avoid excessive heat

Indications & Usage Section

For use as an

first aid antiseptic

pre-operative skin preperation

Inactive Ingredients

Inactive ingredients: Citric acid, glycerin, polysorbate 80, sodium citrate USP, sodium phosphate dibasic, water

Isopropyl Alcohol 70% Prep Pads

Active Ingredient

Purpose

Antiseptic

Uses

For first aid to decrease germs in

minor cuts

scrapes

burns

For preparation of the skin prior to injection

Warnings

For external use only

Flammable - keep away from fire or flame

Do not use

with electrocautery procedures

When using this product do not

get into eyes

apply over large areas of the body

in case of deep or puncture wounds, animal bites or serious burns consult a doctor

Stop use and ask a doctor if

condition persists or gets worse or lasts for more than 72 hours

do not use longer than 1 week unless directed by a doctor

Keep out of reach of children.

If swallowed, get medical help or contact a Poison Control Center right away.

Directions

apply to skin as needed

discard after single use

Other Information

Protect from freezing and avoid excessive heat

Inactive Ingredient

Water

Package Label.principal Display Panel

NDC: 76420-892-01

RX Only

B-LC™

Kit Contains

1 Betamethasone Sodium Phosphate and Betamethasone Acetate 6mg/mL (5mL)

2 Lidocaine HCl Injection, USP 1% Single Dose Vial (5mL)

1 Iodixanol Injection, USP 320mg Iodine/mL Single Dose Bottle (50mL)

1 Povidone-Iodine Swabsticks (3mL Swabs)

4 Isopropyl Alcohol 70% Prep Pads

1 Pair Nitrile Powder Free Sterile Gloves (M)

1 Drape

1 Adhesive Bandage

5 Non Sterile 4x4 Gauze

Needles and Syringes Not Included

1 Dose

Single Use Only

Distributed by:

Enovachem Pharmaceuticals

Torrance, CA 90501

ADULTS and PEDIATRIC PATIENTS 12 YEARS OF AGE AND OLDER IODIXANOL INJECTION DOSING RECOMMENDATIONS FOR INTRAVENOUS CONTRAST ADMINISTRATION
CT of Head or Body ¹	Bolus	75 mL to 150 mL	75 mL to 150 mL	150 mL
Infusion	100 mL to 150 mL	100 mL to 150 mL
Excretory Urography	Normal Renal Function	1 mL/kg	1 mL/kg	100 mL
Venography	Per lower extremity	50 mL to 150 mL		250 mL
CCTA ^1,2	Bolus injection with test bolus ³ or bolus tracking		50 mL to 150 mL ⁴ (4 mL to 7 mL per second)	150 mL

Physical Properties of Iodixanol Injection, USP
Parameter	Concentration (mg Iodine/mL)
Osmolality (mOsmol/kg water)	290	290
Viscosity (cP)	@ 20°C	26.6	12.7
	@ 37°C	11.8	6.3
Density (g/mL)	@ 20°C	1.369	1.314
	@ 37°C	1.356	1.303

Examples of Drugs Associated with Methemoglobinemia:
Class	Examples
Nitrates/Nitrites	nitric oxide, nitroglycerin, nitroprusside, nitrous oxide
Local anesthetics	articaine, benzocaine, bupivacaine, lidocaine, mepivacaine, prilocaine, procaine, ropivacaine, tetracaine
Antineoplastic agents	cyclophosphamide, flutamide, hydroxyurea, ifosfamide, rasburicase
Antibiotics	dapsone, nitrofurantoin, para-aminosalicylic acid, sulfonamides
Antimalarials	chloroquine, primaquine
Anticonvulsants	Phenobarbital, phenytoin, sodium valproate
Other drugs	acetaminophen, metoclopramide, quinine, sulfasalazine

Table 1: Recommended Dosages
Procedure	Lidocaine Hydrochloride Injection (without epinephrine)
*Dose determined by number of dermatomes to be anesthetized (2 to 3 mL/dermatome).
Infiltration
Percutaneous	0.5 or 1	1 to 60	5 to 300
Intravenous regional	0.5	10 to 60	50 to 300
Peripheral Nerve Blocks, e.g.,
Brachial	1.5	15 to 20	225 to 300
Dental	2	1 to 5	20 to 100
Intercostal	1	3	30
Paravertebral	1	3 to 5	30 to 50
Pudendal (each side)	1	10	100
Paracervical
Obstetrical analgesia (each side)	1	10	100
Sympathetic Nerve Blocks, e.g.,
Cervical (stellate ganglion)	1	5	50
Lumbar	1	5 to 10	50 to 100
Central Neural Blocks
Epidural*
Thoracic	1	20 to 30	200 to 300
Lumbar
Analgesia	1	25 to 30	250 to 300
Anesthesia	1.5	15 to 20	225 to 300
	2	10 to 15	200 to 300
Caudal
Obstetrical analgesia	1	20 to 30	200 to 300
Surgical anesthesia	1.5	15 to 20	225 to 300

DISCLAIMER:

"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."

"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."

"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."

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	ARTERIOGRAPHY	IA-DSA1		Maximum Total Dose
Intra-arterial Injection Sites	320 mg Iodine/mL	270 mg Iodine/mL	320 mg Iodine/mL	Maximum Total Dose
Carotid Arteries	10 mL to 14 mL		5 mL to 8 mL	Usually Not to Exceed 175 mL
Vertebral Arteries	10 mL to 12 mL		5 mL to 8 mL	Usually Not to Exceed 175 mL
Right Coronary Artery	3 mL to 8 mL			Usually Not to Exceed 200 mL
Left Coronary Artery	3 mL to 10 mL
Left Ventricle	20 mL to 45 mL
Renal Arteries	8 mL to 18 mL	10 mL to 25 mL	--	Usually Not to Exceed 250 mL
Aortography	30 mL to 70 mL	20 mL to 50 mL	10 mL to 50 mL
Major Branches of Aorta	10 mL to 70 mL	5 mL to 30 mL	2 mL to 10 mL
Aortofemoral Runoffs	20 mL to 90 mL	--	6 mL to 15 mL
Peripheral Arteries	15 mL to 30 mL	--	3 mL to 15 mL

ADULTS and PEDIATRIC PATIENTS 12 YEARS OF AGE AND OLDER IODIXANOL INJECTION DOSING RECOMMENDATIONS FOR INTRAVENOUS CONTRAST ADMINISTRATION
Study Type	Comment	270 mg Iodine/mL	320 mg Iodine/mL	Maximum Total Volume
CT of Head or Body ¹	Bolus	75 mL to 150 mL	75 mL to 150 mL	150 mL
CT of Head or Body ¹	Infusion	100 mL to 150 mL	100 mL to 150 mL
Excretory Urography	Normal Renal Function	1 mL/kg	1 mL/kg	100 mL
Venography	Per lower extremity	50 mL to 150 mL		250 mL
CCTA ^1,2	Bolus injection with test bolus ³ or bolus tracking		50 mL to 150 mL ⁴ (4 mL to 7 mL per second)	150 mL

Age Range	Number of Patients	Elimination half-life
		(hr. ± SD)
Newborn to < 2 months	8	4.1 ± 1.4
2 to 6 months	8	2.8 ± 0.6
6 to 12 months	9	2.4 ± 0.4
1 to 2 years	5	2.3 ± 0.6
2 to 12 years	10	2.3 ± 0.5
Adults	40	2.1 ± 0.1

Product Code	Unit of Sale	Each
381100	NDC 65219-381-10 Unit of 10	NDC 65219-381-03 100 mL single-dose polypropylene bottle
381150	NDC 65219-381-50 Unit of 10	NDC 65219-381-05 150 mL single-dose polypropylene bottle

Procedure	Lidocaine Hydrochloride Injection (without epinephrine)
Procedure	Conc (%)	Vol (mL)	Total Dose (mg)
*Dose determined by number of dermatomes to be anesthetized (2 to 3 mL/dermatome).
Infiltration
Percutaneous	0.5 or 1	1 to 60	5 to 300
Intravenous regional	0.5	10 to 60	50 to 300
Peripheral Nerve Blocks, e.g.,
Brachial	1.5	15 to 20	225 to 300
Dental	2	1 to 5	20 to 100
Intercostal	1	3	30
Paravertebral	1	3 to 5	30 to 50
Pudendal (each side)	1	10	100
Paracervical
Obstetrical analgesia (each side)	1	10	100
Sympathetic Nerve Blocks, e.g.,
Cervical (stellate ganglion)	1	5	50
Lumbar	1	5 to 10	50 to 100
Central Neural Blocks
Epidural*
Thoracic	1	20 to 30	200 to 300
Lumbar
Analgesia	1	25 to 30	250 to 300
Anesthesia	1.5	15 to 20	225 to 300
	2	10 to 15	200 to 300
Caudal
Obstetrical analgesia	1	20 to 30	200 to 300
Surgical anesthesia	1.5	15 to 20	225 to 300

BL-C Kit Dailymed

Drug Classes

Version History

Boxed Warning

Warning: Not For Intrathecal Use

FDA Adverse Reactions

Warning: Not For Intrathecal Use

Recent Major Changes Section

1 Indications And Usage

1.1 Intra-arterial Procedures

1.2 Intravenous Procedures

2 Dosage And Administration

2.1 Important Dosage and Administration Instructions

2.2 Intra-arterial Dosage and Administration

2.3 Intravenous Dosage and Administration

2.4 Dosage in Pediatric Patients Less Than 12 Years of Age

2.5 Instructions for Use with an Automated Contrast Injection System or Contrast Management System for CT of the Head and Body

3 Dosage Forms And Strengths

4 Contraindications

5 Warnings And Precautions

5.1 Risks Associated with Inadvertent Intrathecal Administration

5.2 Hypersensitivity Reactions

5.3 Contrast-Induced 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 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

6 Adverse Reactions

6.1 Clinical Trials Experience

6.2 Post-marketing Experience

6.3 Pediatric Adverse Reactions

7 Drug Interactions

7.1 Drug-Drug Interactions

7.2 Drug-Laboratory Test Interactions

8 Use In Specific Populations

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

10 Overdosage

11 Description

11.1 Chemical Characteristics

11.2 Physical Characteristics

12 Clinical Pharmacology

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 Clinical Studies

14.1 Intra-arterial Administration Studies

14.2 Intravenous Administration Studies

16 How Supplied/storage And Handling

16.1 How Supplied

16.2 Storageand Handling

17 Patient Counseling Information

Description

Clinical Pharmacology

Indications And Usage

Contraindications

Warnings

Serious Neurologic Adverse Reactions with Epidural Administration

General

Cardio-Renal

Endocrine

Infections

Neurologic

Ophthalmic

Precautions

General

Cardio-Renal

Endocrine

Gastrointestinal

Intra-Articular and Soft Tissue Administration

Musculoskeletal

Neuro-Psychiatric