Copper is an essential trace element. In the body, copper is involved in the formation of red blood cells; it is also essential for nerves, bone, and immune system health. Copper is stored primarily in the bones, muscle and the liver, with small amounts found in peripheral tissues. Good food sources of copper include organ meats (especially liver), seafood, beans, nuts, and whole-grains. Recommended dietary allowances (RDA) have been established in most age groups. Copper deficiency is seldom observed in humans as dietary intake often exceeds dietary requirements. Oral dietary supplementation is not normally required. Patients receiving total parenteral nutrition (TPN) require trace element supplementation to prevent deficiency. Copper deficiency was the first trace element deficiency associated with patients receiving chronic total parenteral nutrition (TPN). Copper is available in oral dietary nutritional supplements, including some multivitamins, and as a prescription parenteral drug product for intravenous use; the parenteral product is intended for use as an additive to solutions for total parenteral nutrition (TPN).
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
-Copper chloride 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.
-Contains no bacteriostat; use within 24 hours and discard any remaining drug. 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.
Acute adverse reactions from excess copper supplementation may include abdominal pain or cramps, diarrhea, nausea/vomiting and dysgeusia.
Excessive intake of copper may lead to hepatotoxicity. A few cases have been reported to occur in those chronically exceeding upper tolerable intakes for several years. Acute copper overdose symptoms may include hemolysis and liver toxicity, including hepatic necrosis which may be fatal. Hepatotoxicity, including jaundice, is rare in the absence of genetic defects in copper homeostasis, like Wilson's disease or Indian Childhood Cirrhosis. Chelation therapy may be necessary in symptomatic patients.
Copper toxicity or excessive intake of copper is rare but may lead to clinical symptoms. Acute copper overdose symptoms may include prostation, behavioral changes, diarrhea, progressive marasmus, hypotonia, photophobia, liver toxicity, and peripheral edema. These symptoms have been reported with a serum copper concentration of 286 mcg/dL. Symptoms of overdosage from copper given at 1.5 mg/day are considered unlikely. Chelation therapy may be necessary in symptomatic patients. Chelation therapy, such as D-pencillamine, has been effective as an antidote.
Patients with hepatic disease, biliary tract disease, or biliary obstruction may retain copper since copper is primarily eliminated via the bile; these patients may require dose reduction or possible discontinuation of copper. Serum copper concentrations may help guide the need for supplementation in these patients. It is not recommended to administer copper to a patient with Wilson's Disease, a genetic disease of copper metabolism. In patients with genetic disorders affecting copper metabolism, such as Wilson's disease, Indian childhood cirrhosis (ICC), or idiopathic copper toxicosis (ICT), copper supplementation may worsen the disease.
Copper injection should be used cautiously in patients with renal impairment or renal failure. Copper 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.
Administration of copper in the absence of zinc may cause a decrease in plasma zinc concentrations, and contribute to zinc deficiency. In addition, administration of zinc in the absence of copper may cause a decrease in serum copper concentrations. Monitor plasma zinc and copper concentrations periodically in patients receiving chronic parenteral nutrition.
Copper injection can be administered intravenously only after dilution. Direct intramuscular administration or intravenous administration of copper injection into a peripheral vein is contraindicated since the acidic pH (pH range 1.5 to 2.5) of the solution may cause considerable tissue irritation or infusion phlebitis.
Copper injection should be given during pregnancy only if clearly indicated and if the anticipated benefits outweigh the possible risks. It is not known whether copper 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 copper injection. Adverse effects have not been reported with the normal daily intake of copper within the recommended dietary allowance (RDA) for a pregnant female. If oral copper supplementation is needed during pregnancy, do not exceed the Tolerable Upper Intake Level (UL) of 8 mg/day for women 14 to 18 years old or the UL of 10 mg/day for women 19 years or older.
According to the manufacturer, it is not known whether copper injection is excreted in human milk. Copper injection should be used cautiously in women who are breast-feeding their infants. Adverse effects have not been reported with the normal daily intake of copper within the recommended dietary allowance (RDA) for a lactating female. If oral copper supplementation is needed for women who are breast-feeding, do not exceed the Tolerable Upper Intake Level (UL) of 8 mg/day for women 14 to 18 years old or the UL of 10 mg/day for women 19 years or 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.
Limited data is available on the safety of using copper injection in neonates and infants weighing less than 1,500 grams; these patients may have increased requirements because of their low body reserves and increased requirements for growth. Copper injection should be used cautiously in the parenteral nutrition dependent neonate, especially premature neonates. Copper 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 copper deficiency:
-for nutritional supplementation to prevent copper deficiency and maintain nutritional status in patients receiving parenteral nutrition (PN):
Intravenous dosage:
Adults: 0.3 to 0.5 mg/day IV is recommended by guidelines. 0.5 to 1.5 mg/day IV is the FDA-approved dosage. However, in a study of long-term PN patients, higher doses such as 1 mg/day were shown to result in levels above the normal range in approximately 22.5% of patients. In a study of PN patients, 0.15 mg/day appeared to be an optimal dose for patients with cholestasis, and in patients with diarrhea, 0.4 to 0.5 mg/day appeared to maintain balance. Increased copper losses may occur with nasogastric suction, and patients with burns may require additional copper.
Adolescents: 200 to 500 mcg/day IV.
Infants and Children: 20 mcg/kg/day (Max: 500 mcg/day) IV.
Neonates: 20 mcg/kg/day IV. Some infants, due to co-morbid conditions, require close monitoring of serum copper concentrations to determine the adequacy of supplementation added to TPN.
-for nutritional supplementation to provide the recommended dietary allowance (RDA) in healthy individuals:
Oral dosage:
Adults 19 years and older: 900 mcg PO per day.
Pregnant Females: 1 mg PO per day.
Lactating Females: 1.3 mg PO per day.
Adolescents 14 to 18 years: 890 mcg PO per day.
Children and Adolescents 9 to 13 years: 700 mcg PO per day.
Children 4 to 8 years: 440 mcg PO per day.
Children 1 to 3 years: 340 mcg PO per day.
Infants 7 to 11 months: 220 mcg PO per day is the Adequate Intake (AI). No RDA is established.
Infants 1 to 6 months: 200 mcg PO per day is the Adequate Intake (AI). No RDA is established.
Neonates: 200 mcg PO per day is the Adequate Intake (AI). No RDA is established.
Therapeutic Drug Monitoring:
Weekly monitoring of copper plasma levels is suggested as a guideline for subsequent administration of cupric chloride injection. The normal plasma range for copper is approximately 80 to 160 mcg/100 mL. In patients receiving long-term TPN, twice monthly serum assays for copper and/or ceruloplasmin are recommended. Ceruloplasmin is a cuproenzyme and therefore ceruloplasmin assays may be depressed secondary to copper deficiency.
Maximum Dosage Limits:
The following are recommended tolerable upper intake levels (ULs) for oral dietary intake and the usual maximum daily dosing for PN supplementation.
-Adults
1.5 mg/day IV per FDA-approved labeling; however, guidelines recommend maximum dose of 0.5 mg/day IV; 10 mg/day PO.
-Geriatric
1.5 mg/day IV per FDA-approved labeling; however, guidelines recommend maximum dose of 0.5 mg/day IV; 10 mg/day PO.
-Adolescents
14 to 17 years: 500 mcg/day IV; 8 mg/day PO.
13 years: 500 mcg/day IV; 5 mg/day PO.
-Children
9 to 12 years: 20 mcg/kg/day (Max: 500 mcg/day) IV; 5 mg/day PO.
4 to 8 years: 20 mcg/kg/day (Max: 500 mcg/day) IV; 3 mg/day PO.
1 to 3 years: 20 mcg/kg/day IV; 1 mg/day PO.
-Infants
20 mcg/kg/day IV. Tolerable oral upper intake level has not been established.
-Neonates
20 mcg/kg/day IV. Tolerable oral upper intake level has not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; however, copper is primarily eliminated in the bile and doses should be decreased or omitted in patients with significant cholestasis or hepatic dysfunction. In 1 study, 0.15 mg/day IV appeared to be an optimal dose for adults with cholestasis. Monitor copper concentrations to guide the need for supplementation and dose adjustment.
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 copper concentrations to guide need for supplementation. Urinary copper excretion is normally very low (less than 0.1 mg/day). As with other trace elements, renal dysfunction can lead to increased urinary losses.
*non-FDA-approved indication
Trientine: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of trientine. However, iron deficiency may develop, especially in children and menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but since iron and trientine each inhibit oral absorption of the other, 2 hours should elapse between administration of trientine and iron doses.
Copper is important for proper functioning of many metalloenzymes including ceruloplasmin, ferroxidase II, lysyl oxidase, monoamine oxidase, zinc-copper superoxide dismutase, tyrosinase, dopamine-beta-hydroxylase, and cytochrome-c-oxidase. Physiologically, copper is involved in erythropoiesis and leukopoiesis , bone mineralization, elastin and collagen cross-linking, oxidative phosphorylation, catecholamine metabolism, melanin formation, and antioxidant protection of cells. Copper may also play a role in iron turnover, ascorbic acid metabolism, phospholipid metabolism, myelin formation, glucose homeostasis, and cellular immune defense. Clinical manifestations of deficiency include microcytic, hypochromic anemia, neutropenia, skeletal demineralization and osteoporosis, depigmentation of hair, and skin pallor. In addition, leukopenia, depressed ceruloplasmin levels, impaired transferrin formation, and secondary iron deficiency can occur from copper deficiency. In children with acquired copper deficiencies, vascular aneurysms, central nervous system abnormalities, growth retardation, hypotonia, and hypothermia may occur.
Copper is administered orally and intravenously. Oral absorption occurs primarily in the small intestine with lesser absorption in the stomach. Excretion of copper into the gastrointestinal tract regulates copper homeostasis; greater excretion is the result of increased absorption. The skeleton and muscles contain the majority of copper that is in the body. The liver maintains plasma copper concentrations. Excretion of copper is through the bile (80%), directly through the intestinal wall (16%) and minimally in the urine.
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 copper doses because copper is primarily eliminated in the bile.