Mangafodipir (Systemic)


VA CLASSIFICATION
Primary: DX900

Commonly used brand name(s): Teslascan.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Diagnostic aid, paramagnetic (liver disorders)—

Indications

Accepted

Liver imaging, magnetic resonance—Mangafodipir is indicated for enhancement of the T1-weighted magnetic resonance imaging (MRI) images used in the detection, localization, characterization, and evaluation of lesions of the liver {01}.

Note: Although more lesions are generally visualized on contrast-enhanced images than on unenhanced images, lesions seen on unenhanced images may not all be seen on contrast-enhanced images. Possible causes include changes in imaging parameters, patient motion, misregistration, and effects of the contrast agent. {01}



Pharmacology/Pharmacokinetics

Note: Each of the two components of mangafodipir, fodipir and manganese (II), has different pharmacokinetics (including biotransformation and elimination) {01}.


Physicochemical characteristics:

Chemical group—
    Complex formed between a chelating agent (fodipir) and a paramagnetic metal ion (manganese [II]) {01}.
Molecular weight—
    Mangafodipir trisodium: 757.33 {01}


Osmolality
    298 mOsmol per kg of water {01}.


pH
    8.8 {01}.

Mechanism of action/Effect:

Mangafodipir shortens the spin lattice (longitudinal) relaxation time (T1) of targeted tissues during magnetic resonance imaging (MRI), leading to an increase in signal intensity (brightness) of the tissues {01}.

After administration of mangafodipir, hepatic lesions may present in a number of different patterns of contrast enhancement, indicating hepatocellular (homogeneous, inhomogeneous, or central enhancement) or nonhepatocellular (peripheral or no enhancement) disorders {01}. Hepatic malignancy cannot be distinguished by the pattern of enhancement or by the presence or absence of enhancement {01}.

Protein binding:

Mangafodipir is not plasma protein–bound in vitro ; however, manganese (II) and manganese (III) are bound to plasma proteins in vitro {01}.

Biotransformation:

Involves dephosphorylation reactions, by which removal of two phosphate groups and the exchange of the manganese ion for an endogenous zinc ion result in two major metabolites (manganese dipyridoxyl ethylenediamine diacetic acid [MnPLED] and zinc dipyridoxyl ethylenediamine diacetic acid [ZnPLED] {01}). By 24 hours after the injection, MnPLED and ZnPLED represent 12% and 57%, respectively, of the administered dose {01}.

Half-life:


Distribution:

Manganese (II) ion: In healthy subjects and those with hepatic function impairment—24.4 ± 7.7 minutes. {01}



Elimination:

Fodipir: 2.09 hours {01}.

Manganese (II) ion:

• Healthy subjects—10.1 ± 20.3 hours {01}.


• With hepatic function impairment—26.7 ± 19 hours {01}.



Onset of action:

Increase in T1 signal intensity—Within 1 to 3 minutes {01}.

Time to peak concentration:


Plasma:

MnPLED: Within 10 minutes {01}.

ZnPLED: Within 20 minutes {01}.


Note: Mangafodipir trisodium is not detectable in plasma after 2 hours {01}. MnPLED is not detectable after 1 hour and ZnPLED concentrations decrease slowly {01}.


Peak body concentration

Manganese—A single injection of mangafodipir approximately doubles the total body store of manganese before elimination occurs. (The usual total human body store of manganese in adults is 20 mg, most of that from dietary intake of 2 to 5 mg per day). {01}

Time to peak diagnostic effect

Time to steady-state enhancement of T1 signal intensity—5 to 10 minutes {01}.

Duration of action:

Enhancement of hepatic T1 signal intensity—Up to 24 hours after injection {01}.

Elimination:
    The following information is based on studies with radiolabeled mangafodipir trisodium in healthy volunteers {01}.


Fodipir—
        Renal: 92% over 24 hours {01}.
        Fecal: Negligible (0.3%) {01}.

Note: Total plasma clearance of radioactivity has been found to be 11.6 liters per hour {01}.




Manganese (II) ion—
        Renal: Approximately 15% within the first 24 hours after the injection {01}.
        Fecal: 59% over the 5 days following the first 24 hours after the injection {01}.

Note: The remainder of the manganese (II) ion is eliminated gradually in the urine and feces {01}.




In dialysis—
        Dialyzability of mangafodipir or its metabolites has not been studied {01}.



Precautions to Consider

Carcinogenicity

Long-term animal studies have not been done {01}.

Mutagenicity

Mangafodipir was not found to be mutagenic in the bacterial reverse mutation assay, the CHO/HGPRT forward mutation assay, the CHO chromosome aberration assay, and the in vivo mouse micronucleus assay. It was positive in an in vitro mouse BALB/c-3T3 assay, but negative on a repeat of the test; the assays were performed with the same final concentrations of mangafodipir in the culture medium. {01}

Pregnancy/Reproduction
Fertility—
Studies in male and female rats at doses of up to 100 micromoles per kg of body weight (micromoles/kg) (3.33 times the clinical dose based on body surface area, 20 times the dose based on body weight) found no effects on reproductive performance {01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.

In studies in rats, radiolabeled manganese was found to cross the placenta and appear in the fetus. Radioactivity was detected in the liver and bones of the fetus at least 24 hours after the injection. Manganese has been reported to enter nerve terminals and accumulate in nervous tissue, and may be associated with neurotoxicity in fetuses. {01}

Studies in rats given 12 consecutive daily injections of 10, 20, and 40 micromoles/kg on days 6 through 17 of gestation found teratogenicity (increased incidence of skeletal malformations) and fetotoxicity (decreased fetal body weight) in the offspring, without toxicity in the dams. No adverse effects were found in rat fetuses at the maternal doses of 5 micromoles per kg per day (micromoles/kg/day) (0.16 of the single imaging dose based on body surface area and the same as the imaging dose based on body weight). Skeletal abnormalities also were found in 20 to 60% of the litters at the lowest daily dose used (20 micromoles/kg; 0.64 times the single imaging dose based on body surface area, 4 times the dose based on body weight) in a study in rats given 3 consecutive daily doses, at each of the four 3-day intervals studied. Studies in rabbits given 13 consecutive daily injections of 40 and 60 micromoles/kg on days 6 through 18 of gestation found embryotoxicity and fetotoxicity (increased postimplantation losses and resorptions, and decreased number of viable fetuses) in the offspring, without toxicity in the dams. No adverse effects were found in rabbit fetuses at the maternal doses of 20 micromoles/kg (each daily dose was 1.33 times the single imaging dose based on body surface area, 4 times the dose based on body weight). {01}

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether mangafodipir is distributed into breast milk. However, manganese has been reported to be distributed into breast milk. In addition, neonates have higher intestinal absorption and bioavailability of manganese than adults, although the relationship between bioavailability from breast milk and toxicity is unknown. Because of the risk of adverse effects in the neonate from manganese exposure, it is recommended that discontinuation of nursing be considered until mangafodipir and manganese are cleared from breast milk. {01}

Pediatrics

Appropriate studies on the relationship of age to the effects of mangafodipir have not been performed in the pediatric population. Safety and efficacy in children younger than 12 years of age have not been established. {01}



Adolescents

Appropriate studies on the relationship of age to the effects of mangafodipir have not been performed in the adolescent population. However, safety and efficacy are expected to be the same as in adults. {01}


Geriatrics


Appropriate studies on the relationship of age to the effects of mangafodipir have not been performed in the geriatric population {01}.


Pharmacogenetics

Studies have not been done {01}.

Drug interactions and/or related problems
Studies have not been done {01}.


Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Bilirubin assay and
Ferritin assay and
Iron assay and
Zinc assay    (transmetalation of manganese may occur; extent of possible effect on these assays is unknown {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Allergies, history of or{01}
» Allergic reactions to contrast media, history of or{01}
» Immune system disorders, history of{01}    (increased risk of allergic reaction; it is recommended that patients be observed for several hours after mangafodipir administration {01})


Hepatic function impairment    (effect on hepatobiliary elimination unknown; caution is recommended {01})


» Nausea or vomiting, existing or
» Inability to tolerate vomiting, such as:
Inability to roll over to prevent aspiration
Reflux esophagitis, especially if increased in the supine position    (increased risk from mangafodipir-induced nausea and vomiting {01})


Renal function impairment    (effect on renal elimination via glomerular filtration is unknown; caution is recommended {01})


» Sensitivity to mangafodipir, fodipir, or manganese


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Allergic or anaphylactic reaction{01} (itching; shortness of breath; skin rash or hives; swelling of face)
    
chest pain{01}
    
palpitations{01} (irregular heartbeat)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Injection site reaction (redness{01}; warmth{01})—mild to moderate{01}
    
nausea and/or vomiting

Note: Nausea and/or vomiting may last from several minutes to several hours {01}.


Incidence less frequent
    
Abdominal or stomach pain{01}
    
dizziness{01}
    
headache{01}
    
injection site reaction (coldness{01}; feeling of pressure{01}; pain{01})—mild to moderate





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
No clinical consequences of mangafodipir overdosage have been reported {01}.

Treatment of overdose
Support of vital functions {01}.

Supportive care, prompt {01}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Mangafodipir (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Description of use
Action in the body: Accumulates in normal liver cells, thus creating a contrast between abnormal tissue and normal liver tissue

Before having this test
»   Conditions affecting use, especially:
Sensitivity to mangafodipir, fodipir, or manganese

Pregnancy—Teratogenic, embryotoxic, and fetotoxic in animals; potential for manganese-caused neurotoxicity





Breast-feeding—Possible need to discontinue breast-feeding
Other medical problems, especially history of allergies or allergic reactions to contrast media, history of immune system disorders, existing nausea or vomiting, or inability to tolerate nausea or vomiting


Side/adverse effects
Signs of potential side effects, especially injection site reaction, allergic or anaphylactic reaction, chest pain, and palpitations

Frequently causes nausea and vomiting, which may be prolonged


General Dosing Information
It is recommended that mangafodipir be administered to patients only under the supervision of a physician experienced in the imaging procedure. {01}

If nondisposable administration equipment is used, scrupulous care is recommended to prevent contamination with residual traces of cleansing agents {01}.

It is recommended that equipment and medications necessary for treatment of a possible anaphylactic reaction or other complications of the procedure be available during each administration of mangafodipir {01}.

Imaging procedures can begin within minutes after injection {01}.

If necessary, repeat images can be obtained for up to 24 hours after the original injection without reinjection of mangafodipir {01}.


Parenteral Dosage Forms

MANGAFODIPIR TRISODIUM INJECTION

Usual adult and adolescent dose
Liver imaging, magnetic resonance
Intravenous (peripheral), over approximately one minute, 5 micromoles per kg of body weight {01}.


Note: The safety of repeat injections has not been established {01}.


Usual adult prescribing limits
The dose should not exceed 15 mL {01}.

Usual pediatric dose
Liver imaging, magnetic resonance
Children 12 years of age and older: See Usual adult and adolescent dose {01}.
Children less than 12 years of age: Safety and efficacy have not been established {01}.


Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


50 micromoles per mL (37.9 mg per mL) (Rx) [Teslascan (ascorbic acid 2 mg per mL) (sodium chloride 2 mg per mL) (fodipir 0.25 mg per mL)]

Note: Teslascan contains 2.75 mg of chelated manganese per mL {01}.


Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F) {01}. Protect from freezing {01}.

Note: Store vials on their side in the original carton; do not store the vials upright, which may lead to oxidation or discoloration {01}.


Stability:
The injection does not contain any preservative {01}. Any unused portion of the injection should be discarded {01}.

Incompatibilities:
Mixture of contrast agents with other medications is not recommended because of the potential for chemical incompatibility {01}. If mangafodipir is injected through a plastic tubing, it is recommended that the injection be followed by a flush with 5 mL of 0.9% sodium chloride solution {01}.

Note: Do not use if the product has been frozen {01}.




Developed: 09/10/1998



References
  1. Teslascan package insert (Nycomed—US), Rev 12/97.
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