Gadodiamide

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# Black Box Warning

# Overview
Gadodiamide is a gadolinium-based MRI contrast agent that is FDA approved for the procedure of visualizing lesions with abnormal vascularity in the brain, spine, and associated tissues and facilitate the visualization of lesions with abnormal vascularity within the thoracic, abdominal, pelvic cavities, and the retroperitoneal space. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include nausea, headache, dizziness.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

# Indications
CNS (Central Nervous System)
- Gadodiamide is a gadolinium-based contrast agent indicated for intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues.
Body (Intrathoracic , Intra-abdominal, Pelvic and Retroperitoneal Regions)
- Gadodiamide is a gadolinium-based contrast agent indicated for intravenous use in MRI to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space.

# Dosage
CNS (Central Nervous System)
- The recommended dose of Gadodiamide is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection.
Body (Intrathoracic , Intra-abdominal, Pelvic and Retroperitoneal Regions)
- For imaging the kidney, the recommended dose of Gadodiamide is 0.1 mL/kg (0.05 mmol/kg). For imaging the intrathoracic (noncardiac), intra-abdominal, and pelvic cavities, the recommended dose of Gadodiamide is 0.2 mL/kg (0.1 mmol/kg).
Dosage Chart
Dosing Guidelines
- Inspect Gadodiamide visually for particulate matter and discoloration before administration, whenever solution and container permit.
- Do not use the solution if it is discolored or particulate matter is present.
- Draw Gadodiamide into the syringe and use immediately. Discard any unused portion of Gadodiamide Injection.
- To ensure complete delivery of the desired volume of contrast medium, follow the injection of Gadodiamide with a 5 mL flush of 0.9% sodium chloride, as provided in the Prefill Plus needle-free system. Complete the imaging procedure within 1 hour of administration of Gadodiamide.

# DOSAGE FORMS AND STRENGTHS
- Sterile aqueous solution for intravenous injection; 287 mg/mL.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Gadodiamide in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Gadodiamide in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)

# Indications
CNS (Central Nervous System)
- Gadodiamide is a gadolinium-based contrast agent indicated for intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues.
Body (Intrathoracic , Intra-abdominal, Pelvic and Retroperitoneal Regions)
- Gadodiamide is a gadolinium-based contrast agent indicated for intravenous use in MRI to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space.

# Dosage
CNS (Central Nervous System)
- Pediatric Patients (2-16 years): The recommended dose of gadodiamide is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection.
Body (Intrathoracic , Intra-abdominal, Pelvic and Retroperitoneal Regions)
- Pediatric Patients (2-16 years of age):For imaging the kidney, the recommended dose of gadodiamide is 0.1 mL/kg (0.05 mmol/kg). For imaging the intrathoracic (noncardiac), intra-abdominal, and pelvic cavities, the recommended dose of gadodiamide is 0.2 mL/kg (0.1 mmol/kg).
Dosage Chart
Dosing Guidelines
- Inspect gadodiamide visually for particulate matter and discoloration before administration, whenever solution and container permit.
- Do not use the solution if it is discolored or particulate matter is present.
- Draw gadodiamide into the syringe and use immediately. Discard any unused portion of gadodiamide Injection.
- To ensure complete delivery of the desired volume of contrast medium, follow the injection of gadodiamide with a 5 mL flush of 0.9% sodium chloride, as provided in the Prefill Plus needle-free system. Complete the imaging procedure within 1 hour of administration of gadodiamide.

# DOSAGE FORMS AND STRENGTHS
- Sterile aqueous solution for intravenous injection; 287 mg/mL.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Gadodiamide in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Gadodiamide in pediatric patients.

# Contraindications
- Gadodiamide is contraindicated in patients with:
- Chronic, severe kidney disease (glomerular filtration rate, GFR < 30 mL/min/1.73m2), or
- Acute kidney injury
- Prior hypersensitivity reaction to gadodiamide

# Warnings
There is limited information regarding Gadodiamide Warnings' in the drug label.

# Adverse Reactions

## Clinical Trials Experience
- The following adverse reactions are discussed in greater detail in other sections of the label:
- Nephrogenic systemic fibrosis.
- Hypersensitivity reactions.
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Clinical Studies Experience (Adults)
- In clinical studies 1160 patients were exposed to gadodiamide. The most frequent adverse reactions were nausea, headache, and dizziness that occurred in 3% or less of the patients. The majority of these reactions were of mild to moderate intensity.
- The following adverse reactions occurred in 1% or less of patients:
- Application Site Disorders: Injection site reaction.
- Autonomic Nervous System Disorders: Vasodilation.
- Body as a Whole-General Disorders: Anaphylactoid reactions (characterized by cardiovascular, respiratory, and cutaneous symptoms), fever, hot flushes, rigors, fatigue, malaise, pain, syncope.
- Cardiovascular Disorders: Cardiac failure, rare arrhythmia and myocardial infarction resulting in death in patients with ischemic heart disease, flushing, chest pain, deep thrombophlebitis.
- Central and Peripheral Nervous System Disorders: Convulsions including grand mal, ataxia, abnormal coordination, paresthesia, tremor, aggravated multiple sclerosis (characterized by sensory and motor disturbances), aggravated migraine.
- Gastrointestinal System Disorders: Abdominal pain, diarrhea, eructation, dry mouth/vomiting, melena.
- Hearing and Vestibular Disorders: Tinnitus.
- Liver and Biliary System Disorders: Abnormal hepatic function.
- Musculoskeletal System Disorders: Arthralgia, myalgia.
- Respiratory System Disorders: Rhinitis, dyspnea.
- Skin and Appendage Disorders: Pruritus, rash, erythematous rash, sweating increased, urticaria.
- Special Senses, Other Disorders: Taste loss, taste perversion.
- Urinary System Disorders: Acute reversible renal failure.
- Vision Disorders: Abnormal vision.
Clinical Studies Experience (Pediatrics)
- In the 97 pediatric patients in CNS studies with gadodiamide and the 144 pediatric patients in published literature, the adverse reactions were similar to those reported in adults.

## Postmarketing Experience
- Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- The following adverse reactions have been identified during the postmarketing use of Gadodiamide:
- Nervous System Disorders: Inadvertent intrathecal use causes convulsions, coma, paresthesia, paresis. Convulsions have also been reported with intravenous use in patients with and without a history of convulsions or brain lesions.
- General Disorders: Nephrogenic Systemic Fibrosis (NSF).
- Renal and Urinary System Disorders: In patients with pre-existing renal insufficiency: acute renal failure, renal impairment, blood creatinine increased.

# Drug Interactions
- Specific drug interaction studies have not been conducted.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Pregnancy Category C: Gadodiamide has been shown to have an adverse effect on embryo-fetal development in rabbits at dosages as low as 0.5 mmol/kg/day for 13 days during gestation (approximately 0.6 times the human dose based on a body surface area comparison). These adverse effects are observed as an increased incidence of flexed appendages and skeletal malformations which may be due to maternal toxicity since the body weight of the dams was reduced in response to gadodiamide administration during pregnancy. In rat studies, fetal abnormalities were not observed at doses up to 2.5 mmol/kg/day for 10 days during gestation (1.3 times the maximum human dose based on a body surface area comparison); however, maternal toxicity was not achieved in these studies and a definitive conclusion about teratogenicity in rats at doses above 2.5 mmol/kg/day cannot be made. Adequate and well controlled studies in pregnant women have not been conducted. Gadodiamide should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadodiamide in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Gadodiamide during labor and delivery.

### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, exercise caution when administering Gadodiamide to a nursing woman.

### Pediatric Use
- The safety and efficacy of gadodiamide at a single dose of 0.05 to 0.1 mmol/kg have been established in pediatric patients over 2 years of age based on adequate and well controlled studies of gadodiamide in adults, a pediatric CNS imaging study, and safety data in the scientific literature. However, the safety and efficacy of doses greater than 0.1 mmol/kg and of repeated doses have not been studied in pediatric patients.
- Pharmacokinetics of gadodiamide have not been studied in pediatrics. The glomerular filtration rate of neonates and infants is much lower than that of adults. The pharmacokinetics volume of distribution is also different. Therefore, the optimal dosing regimen and imaging times in patients under 2 years of age have not been established.

### Geriatic Use
- In clinical studies of gadodiamide, 243 patients were between 65 and 80 years of age while 15 were over 80. 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 in the elderly cannot be ruled out. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
- Gadodiamide is excreted by the kidney, and the risk of toxic reactions to gadodiamide is greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, select dose carefully and assess eGFR by laboratory testing before gadodiamide use.

### Gender
There is no FDA guidance on the use of Gadodiamide with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Gadodiamide with respect to specific racial populations.

### Renal Impairment
- Dose adjustments in renal impairment have not been studied. Caution should be exercised in patients with impaired renal insufficiency.

### Hepatic Impairment
- Dose adjustments in hepatic impairment have not been studied.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Gadodiamide in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Gadodiamide in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Intravenous

### Monitoring
There is limited information regarding Monitoring of Gadodiamide in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Gadodiamide in the drug label.

# Overdosage
- Clinical consequences of overdose with gadodiamide have not been reported. The minimum lethal dose of intravenously administered gadodiamide in rats and mice is greater than 20 mmol/kg (200 times the recommended human dose of 0.1 mmol/kg; 67 times the cumulative 0.3 mmol/kg dose). Gadodiamide is dialyzable.

# Pharmacology

## Mechanism of Action
There is limited information regarding Gadodiamide Mechanism of Action in the drug label.

## Structure
- Gadodiamide (gadodiamide) Injection is the formulation of the gadolinium complex of diethylenetriamine pentaacetic acid bismethylamide, and is an injectable, nonionic extracellular enhancing agent for magnetic resonance imaging. Gadodiamide is administered by intravenous injection.
- Gadodiamide is provided as a sterile, clear, colorless to slightly yellow, aqueous solution. Each 1 mL contains 287 mg gadodiamide and 12 mg caldiamide sodium in Water for Injection. The pH is adjusted between 5.5 and 7.0 with hydrochloric acid and/or sodium hydroxide. Gadodiamide contains no antimicrobial preservative. Gadodiamide is a 0.5 mol/L solution of aqua-3-oxo-2,5,8,11-tetraazatridecan-13-oato (3-)-N5, N8, N11, O3, O5, O8, O11, O13] gadolinium hydrate, with a molecular weight of 573.66 (anhydrous), an empirical formula of C16H28GdN5O9xH2O, and the following structural formula:
- Pertinent physicochemical data for gadodiamide are noted below:
- Gadodiamide has an osmolality approximately 2.8 times that of plasma at 37C and is hypertonic under conditions of use.

## Pharmacodynamics
- In magnetic resonance imaging, visualization of normal and pathologic tissue depends in part on variations in the radiofrequency signal intensity. These variations occur due to: changes in proton density; alteration of the spin-lattice or longitudinal relaxation time (T1); and variation of the spin-spin or transverse relaxation time (T2). Gadodiamide is a paramagnetic agent with unpaired electron spins which generate a local magnetic field. As water protons move through this local magnetic field, the changes in magnetic field experienced by the protons reorient them with the main magnetic field more quickly than in the absence of a paramagnetic agent.
- By increasing the relaxation rate, gadodiamide decreases both the T1 and T2 relaxation times in tissues where it is distributed. At clinical doses, the effect is primarily on the T1 relaxation time, and produces an increase in signal intensity. Gadodiamide does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that do not have an abnormal blood-brain barrier (e.g., cysts, mature postoperative scars). However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of gadodiamide in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of gadodiamide in various lesions are not known. There is no detectable biotransformation or decomposition of gadodiamide.

## Pharmacokinetics
- The pharmacokinetics of intravenously administered gadodiamide in normal subjects conforms to an open, two-compartment model with mean distribution and elimination half-lives (reported as mean  SD) of 3.7  2.7 minutes and 77.8  16 minutes, respectively.
- Gadodiamide is eliminated primarily in the urine with 95.4  5.5% (mean  SD) of the administered dose eliminated by 24 hours. The renal and plasma clearance rates of gadodiamide are nearly identical (1.7 and 1.8 mL/min/kg, respectively), and are similar to that of substances excreted primarily by glomerular filtration. The volume of distribution of gadodiamide (200  61 mL/kg) is equivalent to that of extracellular water. Gadodiamide does not bind to human serum proteins in vitro. Pharmacokinetic and pharmacodynamic studies have not been systematically conducted to determine the optimal dose and imaging time in patients with abnormal renal function or renal failure, in the elderly, or in pediatric patients with immature renal function

## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long term animal studies have not been performed to evaluate the carcinogenic potential of gadodiamide. The results of the following genotoxicity assays were negative: in vitro bacterial reverse mutation assay, in vitro Chinese Hamster Ovary (CHO)/Hypoxanthine Guanine Phosphoribosyl Transferase (HGPT) forward mutation assay, in vitro CHO chromosome aberration assay, and the in vivo mouse micronucleus assay at intravenous doses of 27 mmol/kg (approximately 7 times the maximum human dose based on a body surface area comparison). Impairment of male or female fertility was not observed in rats after intravenous administration three times per week at the maximum dose tested of 1.0 mmol/kg (approximately 0.5 times the maximum human dose based on a body surface area comparison).

# Clinical Studies
CNS (Central Nervous System)
- Gadodiamide (0.1 mmol/kg) contrast enhancement in CNS MRI was evident in a study of 439 adults. In a study of sequential dosing, 57 adults received gadodiamide 0.1 mmol/kg followed by 0.2 mmol/kg within 20 minutes (for cumulative dose of 0.3 mmol/kg). The MRIs were compared blindly. In 54/56 (96%) patients, gadodiamide contrast enhancement was evident with both the 0.1 mmol/kg and cumulative 0.3 mmol/kg gadodiamide doses relative to non-contrast MRI.
- In comparison to the non-contrast MRI, increased numbers of brain and spine lesions were noted in 42% of patients who received gadodiamide at any dose. In comparisons of 0.1 mmol/kg versus 0.3 mmol/kg, the results were comparable in 25/56 (45%); in 1/56 (2%) gadodiamide 0.1 mmol/kg dose provided more diagnostic value and in 30/56 (54%) the cumulative gadodiamide 0.3 mmol/kg dose provided more diagnostic value.
- The usefulness of a single 0.3 mmol/kg bolus in comparison to the cumulative 0.3 mmol/kg (0.1 mmol/kg followed by 0.2 mmol/kg) has not been established.
- Gadodiamide as a single 0.1 mmol/kg dose was evaluated in 97 pediatric patients with a mean age of 8.9 (2-18) years referred for CNS MRI. Postcontrast MRI provided added diagnostic information, diagnostic confidence, and new patient management information in 76%, 67%, and 52%, respectively, of pediatrics.
Body (Intrathoracic , Intra-abdominal, Pelvic and Retroperitoneal Regions)
- Gadodiamide was evaluated in a controlled trial of 276 patients referred for body MRI. These patients had a mean age of 57 (9-88) years. Patients received 0.1 mmol/kg gadodiamide for imaging the thorax (noncardiac), abdomen, and pelvic organs, or a dose of 0.05 mmol/kg for imaging the kidney. Pre- and post-gadodiamide images were evaluated blindly for the degree of diagnostic value rated on a scale of "remarkably improved, improved, no change, worse, and cannot be determined." The postcontrast results showed "remarkably improved" or "improved" diagnostic value in 90% of the thorax, liver, and pelvis patients, and in 95% of the kidney patients.
- In a dose ranging study 258 patients referred for body MRI received gadodiamide 0.025, 0.05, 0.1 mmol/kg. The lowest effective dose of Gadodiamide for the kidney was 0.05 mmol/kg.

# How Supplied
- OMNISCAN (gadodiamide) Injection is a sterile, clear, colorless to slightly yellow, aqueous solution containing 287 mg/mL of gadodiamide in rubber stoppered vials and prefilled syringes. OMNSICAN is supplied in the following sizes:
- 5 mL fill in 10 mL vial, box of 10 (NDC 0407-0690-05)
- 10 mL vial, box of 10 (NDC 0407-0690-10)
- 15 mL fill in 20 mL vial, box of 10 (NDC 0407-0690-15)
- 20 mL vial, box of 10 (NDC 0407-0690-20)
- 10 mL fill in 20 mL prefilled syringe, box of 10 (NDC 0407-0690-12)
- 15 mL fill in 20 mL prefilled syringe, box of 10 (NDC 0407-0690-17)
- 20 mL prefilled syringe, box of 10 (NDC 0407-0690-22)
- Prefill PlusTM needle-free system
OMNISCAN 15 mL, box of 10 (NDC 0407-0691-62)
Contains: OMNISCAN 15 mL fill in 20 mL Single Dose Prefilled Syringe and
5 mL 0.9% Sodium Chloride Injection, USP I.V. Flush Syringe
- Prefill PlusTM needle-free system
OMNISCAN 20 mL, box of 10 (NDC 0407-0691-63)
Contains: OMNISCAN 20 mL fill in 20 mL Single Dose Prefilled Syringe and
5 mL 0.9% Sodium Chloride Injection, USP I.V. Flush Syringe
- Protect gadodiamide from strong daylight and direct exposure to sunlight. Do not freeze. Freezing can cause small cracks in the vials, which would compromise the sterility of the product. Do not use if the product is inadvertently frozen.

## Storage
- Store gadodiamide at controlled room temperature 20-25C (68-77F); excursions permitted to 15-30C (59-86F) .

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Patients receiving gadodiamide should be instructed to inform their physician if they:
- Are pregnant or breast feeding, or
- Have a history of renal and/or liver disease, convulsions, asthma or allergic respiratory disorders, or recent administration of gadolinium-based contrast.
- GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF:
- Describe the clinical manifestations of NSF
- Describe procedures to screen for the detection of renal impairment
- Instruct the patients to contact their physician if they develop signs or symptoms of NSF following gadodiamide administration such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain deep in the hip bones or ribs; or muscle weakness.

# Precautions with Alcohol
- Alcohol-Gadodiamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- OMNISCAN

# Look-Alike Drug Names
- A  B

# Drug Shortage Status

# Price