Manganese is an essential trace element. In the body, manganese is stored in mitochondria-rich tissues such as the brain, kidney, pancreas, liver, and skeletal muscle parenchyma. Rich dietary sources include whole grains, cereal products, some vegetables, legumes and nuts. A role for manganese has been postulated for maintaining strong bones. There is no established recommended daily allowance (RDA) for manganese. Instead, adequate intakes (AIs) are representative of the dietary needs of various age groups; in healthy infants the AIs describe the mean intake obtainable via breast milk. Manganese is known to be an important nutrient, but manganese deficiency has not been documented in humans, as dietary intakes often exceed dietary requirements. Oral dietary supplementation is not normally required. Patients receiving parenteral nutrition (PN) require trace element supplementation to prevent deficiency. There is a risk of neurotoxicity in patients receiving PN supplemented with manganese, particularly those receiving higher than recommended doses or those with cholestatic liver disease.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Oral dietary supplements should be administered as directed by the specific product label.
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Manganese injection must be diluted and used as an admixture in parenteral nutrition solutions; do not administer by direct IV infusion.
-Follow proper admixing sequence as related to parenteral nutrition.
-Manganese injection solution contains no preservatives; the vial should be used promptly and in a single operation without any repeated penetrations. Discard unused portion immediately after admixture procedure is completed. After mixing in parenteral nutrition solutions, admixtures are stable for 24 hours under refrigeration; after removal from refrigeration, use solution promptly and complete the infusion within 24 hours. Discard any remaining admixture.
Manganese has been associated with neurotoxicity in adult and pediatric patients on long-term parenteral nutrition receiving manganese at higher than recommended dosages and in association with cholestatic liver disease. However, brain MRI findings and clinical symptoms have also been observed in patients who received manganese at or below the recommended dosage and with normal blood manganese concentrations. In the brain, manganese is concentrated in the basal ganglia, which partially accounts for the regional specificity of neurotoxicity and the resultant symptoms. Neuropsychiatric symptoms, including excitement, irritability, impaired cognition, compulsive behavior (impulse control symptoms), seizures, dystonic reaction, and parkinsonian-like symptoms or pseudoparkinsonism (tremor, dysarthria, mask-face, gait disturbance), have been reported. Regression of symptoms and MRI findings have occurred over weeks to months following discontinuation of manganese in most patients but have not always completely resolved. Monitor patients receiving parenteral nutrition solutions containing manganese for neurologic signs and symptoms and routinely measure whole blood manganese concentrations and liver tests. In case of suspected manganese toxicity or new neuropsychiatric manifestations, temporarily discontinue manganese, check manganese whole blood concentrations, and consider brain MRI evaluation. The risk of serious adverse events occurring from excess oral intake from dietary or supplement sources appears low in otherwise healthy individuals, as long as the recommended tolerable upper intake levels (UL) are not exceeded.
Manganese injection contains aluminum. Thus, aluminum toxicity may occur with prolonged administration in high-risk patients, including those with renal impairment and premature neonates. Premature neonates are at particular risk for aluminum toxicity because of immature renal function, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that patients with renal impairment, who receive parenteral aluminum at rates greater than 4 to 5 mcg/kg/day, may develop aluminum toxicity (CNS and bone toxicity). Tissue loading may occur at lower administration rates.
Patients with hepatic disease, biliary tract disease, or biliary obstruction may retain manganese since manganese is eliminated via the bile; these patients may require dose reduction, dose omission, or possible discontinuation of manganese.
Manganese injection should be used cautiously in patients with renal impairment or renal failure. Manganese injection contains aluminum that may be toxic; patients with impaired kidney function may experience aluminum toxicity with prolonged administration. Research indicates that patients with renal impairment who receive parenteral aluminum at rates greater than 4 to 5 mcg/kg/day may accumulate aluminum at levels associated with CNS and bone toxicity. Tissue loading may occur at lower administration rates.
Manganese has been associated with neurotoxicity in adult and pediatric patients on long-term parenteral nutrition receiving manganese at higher than recommended dosages and in association with cholestatic liver disease. However, brain MRI findings and clinical symptoms have also been observed in patients who received manganese at or below the recommended dosage and with normal blood manganese concentrations. Some adult patients with brain MRI findings reportedly experienced neuropsychiatric symptoms, including changes in mood or memory, seizures and/or parkinsonian-like tremors, dysarthria, mask-face, and halting gait. Some pediatric patients experienced dystonic movements or seizures. Regression of symptoms and MRI findings have occurred over weeks to months following discontinuation of manganese in most patients but have not always completely resolved. Monitor patients receiving parenteral nutrition solutions containing manganese for neurologic signs and symptoms and routinely measure whole blood manganese concentrations and liver tests. In case of suspected manganese toxicity or new neuropsychiatric manifestations, temporarily discontinue manganese, check manganese whole blood concentrations, and consider brain MRI evaluation.
Manganese injection can be administered intravenously only after dilution. Direct intramuscular administration or direct intravenous administration of manganese injection into a peripheral vein is contraindicated since the acidic pH (pH 2.0) of the solution may cause considerable tissue necrosis, irritation, or infusion phlebitis.
Manganese injection should be given during pregnancy only if clearly indicated and if the anticipated benefits outweigh the possible risks. It is not known whether manganese injection can cause fetal harm when administered to a pregnant woman or if the injection can affect reproductive capacity. Animal reproduction studies have not been conducted with manganese injection. Adverse effects have not been reported with the normal daily intake of manganese within the recommended adequate dietary intakes (AI) for a pregnant female. If oral manganese supplementation is needed during pregnancy, do not exceed the Tolerable Upper Intake Level (UL) of 9 mg/day for women 14 to 18 years of age or the UL of 11 mg/day for women 19 years of age and older.
According to the manufacturer, manganese injection should be used cautiously in women who are breast-feeding their infants. It is not known whether manganese injection is excreted in human milk. Adverse effects have not been reported with the normal daily intake of manganese within the recommended adequate dietary intakes (AI) for a lactating female. If oral manganese supplementation is needed for women who are breast-feeding, do not exceed the Tolerable Upper Intake Level (UL) of 9 mg/day for women 14 to 18 years of age or the UL of 11 mg/day for women 19 years of age and older. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Manganese injection should be used cautiously in premature neonates. Biliary excretion of manganese is impaired in premature neonates and dosing must be approached with care in the parenteral nutrition dependent neonate; supplementation should be held when bilirubin levels in the neonate are higher than 2 mg/dL to prevent manganese toxicity. Manganese injection contains aluminum and premature neonates are at particular risk for aluminum toxicity because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Research indicates that premature neonates with impaired kidney function who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
For nutritional supplementation and prevention of manganese deficiency:
-for the prevention of manganese deficiency and maintenance of adequate manganese stores in patients receiving parenteral nutrition (PN):
Intravenous dosage:
Adults: 55 mcg/day IV is recommended by guidelines. Higher doses may be needed in those with established deficiency or those with increased requirements. The FDA-approved dosage is 150 to 800 mcg/day IV. However, manganese toxicity has been reported with these high doses in long-term PN patients.
Infants, Children, and Adolescents: 1 mcg/kg/day (Max: 55 mcg/day) IV is recommended by guidelines for routine supplementation. Higher doses may be needed in those with established deficiency or those with increased requirements. The FDA-approved dosage is 2 to 10 mcg/kg/day IV. However, manganese toxicity has been reported with these high doses in long-term PN patients.
Neonates: 1 mcg/kg/day IV.
-for providing the recommended adequate intake (No RDA is established) of elemental manganese via the diet:
Oral dosage:
Adult Males 19 years and older: 2.3 mg PO per day.
Adult Females 19 years and older: 1.8 mg PO per day.
Pregnant Females: 2 mg PO per day.
Lactating Females: 2.6 mg PO per day.
Adolescent Males 14 to 18 years: 2.2 mg PO per day.
Adolescent Females 14 to 18 years: 1.6 mg PO per day.
Male Children 9 to 13 years: 1.9 mg PO per day.
Female Children 9 to 13 years: 1.6 mg PO per day.
Children 4 to 8 years: 1.5 mg PO per day.
Children 1 to 3 years: 1.2 mg PO per day.
Infants 7 to 11 months: 0.6 mg PO per day.
Infants 1 to 6 months: 0.003 mg PO per day.
Neonates: 0.003 mg PO per day.
Therapeutic Drug Monitoring:
-Monitor manganese whole blood concentrations and liver function tests routinely in patients receiving parenteral nutrition to prevent manganese accumulation.
-Usual reference range for manganese in whole blood is 6 to 12 mcg/L (range: 4.2 to 18 mcg/L, depending on the laboratory and the assay used).
Maximum Dosage Limits:
The following are recommended tolerable intake upper limits (UL) for oral dietary intake and the usual upper limit of daily dosing for parenteral nutrition (PN) supplementation.
-Adults
11 mg/day PO; 800 mcg/day IV is FDA-approved maximum dosage; however, guidelines recommend maximum dosage of 55 mcg/day IV.
-Geriatric
11 mg/day PO; 800 mcg/day IV is FDA-approved maximum dosage; however, guidelines recommend maximum dosage of 55 mcg/day IV.
-Adolescents
14 to 17 years: 9 mg/day PO; 10 mcg/kg/day IV is FDA-approved maximum dosage; however, guidelines recommend maximum dosage of 1 mcg/kg/day (Max: 55 mcg/day) IV.
13 years: 6 mg/day PO; 10 mcg/kg/day IV is FDA-approved maximum dosage; however, guidelines recommend maximum dosage of 1 mcg/kg/day (Max: 55 mcg/day) IV.
-Children
9 to 12 years: 6 mg/day PO; 10 mcg/kg/day IV is FDA-approved maximum dosage; however, guidelines recommend maximum dosage of 1 mcg/kg/day (Max: 55 mcg/day) IV.
4 to 8 years: 3 mg/day PO; 10 mcg/kg/day IV is FDA-approved maximum dosage; however, guidelines recommend maximum dosage of 1 mcg/kg/day IV.
1 to 3 years: 2 mg/day PO; 10 mcg/kg/day IV is FDA-approved maximum dosage; however, guidelines recommend maximum dosage of 1 mcg/kg/day IV.
-Infants
1 mcg/kg/day IV; upper tolerable oral intake level is not established.
-Neonates
1 mcg/kg/day IV; upper tolerable oral intake level is not established.
Patients with Hepatic Impairment Dosing
Liver and/or biliary tract dysfunction may require omission or reduction of manganese doses because manganese is primarily eliminated in the bile.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed; monitor manganese levels to guide need for supplementation since patients with severe renal impairment or renal failure not on dialysis may have higher manganese concentrations. In patients with renal impairment, including premature neonates, prolonged administration of intravenous manganese may produce aluminum toxicity since manganese chloride injection contains aluminum.
*non-FDA-approved indication
There are no drug interactions associated with Manganese products.
Manganese is an essential trace element that serves as an activator for enzymes such as polysaccharide polymerase, liver arginase, cholinesterase, and pyruvate carboxylase. Manganese may also serve as a cofactor in lipid, protein, and carbohydrate metabolism, and is important in bone formation. In animals, manganese deficiency may lead to poor reproductive performance, growth retardation, congenital malformations in offspring, abnormal formation of bone and cartilage, dermatitis, and impaired glucose tolerance. Manganese supplementation during total parenteral nutrition (TPN) helps prevent development of deficiency symptoms, including nausea and vomiting, weight loss, and changes in growth and color of hair.
Manganese is administered orally and intravenously. Manganese is bound to a specific transport protein, transmanganin, a beta-1-globulin. Although manganese is widely distributed, it concentrates in tissues that are rich in mitochondria such as brain, kidney, pancreas, and liver. Assays for manganese in whole blood result in concentrations ranging from 6 to 12 mcg/L. The bile is the primary route of excretion of manganese, but in the event of obstruction, ancillary excretion routes include pancreatic juice, or return into the lumen of the duodenum, jejunum, or ileum. Urinary excretion of manganese is negligible.
Affected cytochrome P450 (CYP450) enzymes and drug transporters: None
-Special Populations
Hepatic Impairment
Liver and/or biliary tract dysfunction may require omission or reduction of manganese doses because manganese is primarily eliminated in the bile.
Renal Impairment
Predialysis patients with chronic renal failure have been noted to have increases in circulating levels of manganese.