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Copper Supplements (Systemic)

This monograph includes information on the following:

1) Copper Gluconate 
2) Cupric Sulfate 

VA CLASSIFICATION
Primary: TN499

Commonly used brand name(s): Cupri-Pak2.

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

Not commercially available in Canada.



Category:


Nutritional supplement (mineral)—

Indications

Accepted

Copper deficiency (prophylaxis and treatment){01}—Copper supplements are indicated in the prevention and treatment of copper deficiency, which may result from inadequate nutrition or intestinal malabsorption, but does not occur in healthy individuals receiving an adequate balanced diet. For prophylaxis of copper deficiency, dietary improvement, rather than supplementation, is advisable. For treatment of copper deficiency, supplementation is preferred. {29}
—Deficiency of copper may lead to hypochromic and microcytic anemias, neutropenia, and bone demineralization. {03} {04} {05} {13} {19}
—Recommended intakes may be increased and/or supplementation may be necessary in the following persons or conditions (based on documented copper deficiency):

• Burns {05}


• Gastrectomy


• Infants—premature {04} {05} {13}


• Intestinal diseases—celiac {04}, diarrhea {03} {04}, sprue {03} {04}


• Malabsorption syndromes associated with pancreatic insufficiency—cystic fibrosis {10}


• Malnutrition, especially protein {03} {04}


• Renal disease—nephrotic syndrome {03} {04}


• Stress, prolonged {05}

—Some unusual diets (e.g., reducing diets that drastically restrict food selection) may not supply minimum daily requirements of copper. Supplementation may be necessary in patients receiving total parenteral nutrition (TPN) {04} {05} {09} or undergoing rapid weight loss or in those with malnutrition, because of inadequate dietary intake.
—Recommended intakes may be increased by the following: penicillamine, trientine, oral zinc supplements.

Unaccepted
Copper supplements should not be used as emetics, as death has been reported.

A potential role for copper supplements in the treatment of rheumatoid arthritis and psoriasis has not been proven. {29}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Copper gluconate: 453.84 {32}
    Copper sulfate: 249.7 {31}
    Elemental copper: 63.54 {05}

Mechanism of action/Effect:

Copper is necessary for the proper functioning of many metalloenzymes, including ceruloplasmin, monoamine oxidase, ferroxidase II, tyrosinase, dopamine beta-hydroxylase, and cytochrome-C-oxidase. {05} {06} Physiological functions that are copper dependent include oxidation of iron, erythro- and leukopoiesis, bone mineralization, elastin and collagen cross-linking, oxidative phosphorylation, catecholamine metabolism, melanin formation, myelin formation, glucose homeostasis, and antioxidant protection of the cell. {05} {21}

Absorption:

Approximately 40 to 60% of dietary copper is absorbed, primarily from the stomach and duodenum. {01} Copper absorption increases in copper deficiency and decreases with adequate copper status. {28} After absorption, copper is bound to the carrier protein, metallothionein {28}.

Protein binding:

Copper is 90 to 95% bound to ceruloplasmin, 1 to 2% bound to amino acids or free, and the remaining is reversibly bound to albumin. {01}


Storage

Copper is stored primarily in the liver, with small amounts found in peripheral tissues. {05}

Biotransformation:

Hepatic. {05}

Elimination:
    Primarily in bile, with small amounts eliminated in urine, sweat, and epidermal shedding. {01} {05}


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Problems in humans have not been documented with intake of normal daily recommended amounts. However, adequate and well-controlled studies in humans have not been done.

Studies have not been done in animals.

FDA Pregnancy Category C (parenteral copper). {01}

Breast-feeding

Problems in humans have not been documented with intake of normal daily recommended amounts.

Pediatrics

Problems in pediatrics have not been documented with intake of normal daily recommended amounts.

Infusion of free amino acids of the total parenteral nutrition (TPN) solution has been reported to produce copper diuresis in infants. {05} {30}

Copper injection that contains benzyl alcohol as a preservative should not be used in newborn and immature infants. The use of benzyl alcohol in neonates has been associated with a fatal toxic syndrome consisting of metabolic acidosis and CNS, respiratory, circulatory, and renal function impairment.


Geriatrics


Problems in geriatrics have not been documented with intake of normal daily recommended amounts.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following, depending on the amount present, may also interact with copper supplements.

Copper-containing preparations, other    (concurrent use with copper supplements may increase serum copper concentrations)


» Penicillamine or{21}{22}
» Trientine{23}    (copper chelation by penicillamine or trientine may lead to decreased serum copper concentrations; penicillamine or trientine should be given 2 hours before copper supplements {23})


» Zinc supplements, oral    (large doses of zinc supplements may inhibit copper absorption in the intestine; copper supplements should be taken 2 hours after zinc supplements {03} {15} {20})


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).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Wilson's disease{01}{05}    (condition may be exacerbated)


Risk-benefit should be considered when the following medical problems exist
» Biliary tract disease or{01}{05}
Hepatic disease{01}    (may cause an accumulation of copper, since copper is normally eliminated in bile; a reduction in copper dosage may be necessary {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Ceruloplasmin concentrations, serum or{01}{05}{21}{27}
» Copper concentrations, serum, plasma, or urinary{01}{05}{21}{27}    (determinations recommended monthly {35} {36}; however, these monitoring parameters are subject to many variables and may not be good indicators of copper overload {05})




Overdose
For specific information on the agents used in the management of copper overdose, see:
   • Calcium Edetate Disodium (Systemic) monograph;
   • Dimercaprol (Systemic) monograph; and/or
   • Penicillamine (Systemic).
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
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:


Side/Adverse Effects
    
Coma{24}{25}
    
diarrhea {24}{25}
    
epigastric pain and discomfort (heartburn){17}{24}{25}
    
hematuria (blood in urine; lower back pain; pain or burning while urinating){17}
    
hepatotoxicity (black or bloody vomit; severe or continuing headache; loss of appetite; severe or continuing nausea; pain in abdomen; yellow eyes or skin){17}{25}
    
hypotension (dizziness or fainting)
    
jaundice (yellow eyes or skin){17}{24}
    
metallic taste {17}{24}
    
vomiting
{24}{25}

Treatment of overdose
Dilution with milk or water {25} {26}


To decrease absorption:
Emptying stomach contents by emesis or gastric lavage if patient is not already vomiting {25} {26}



Specific treatment:
If patient is symptomatic, instituting chelation therapy with one of the following chelating agents:


• Calcium edetate disodium—

• Intravenous, 50 mg per kg of body weight (mg/kg) a day for 5 days; course may be repeated after a 2-day interval {26}.


• Intramuscular, 12.5 mg/kg every 4 to 6 hours for 5 days; course may be repeated after a 2-day interval. {26}



• Dimercaprol— {17}

• Intramuscular, 3 to 5 mg/kg every 4 hours for 2 days, then 3 mg/kg every 6 hours for 2 days, then 3 mg/kg every 12 hours for up to 7 days or until recovery is complete {25}.



• Penicillamine—Orally, 10 mg/kg in 4 divided doses a day (not to exceed 1 gram a day) for no longer than 1 week; {25} if symptoms recur, allow 3 to 5 days before resuming therapy.



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

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

Description of use
Description should include function in the body, signs of deficiency, conditions that may cause copper deficiency, unproven uses


Importance of diet
Importance of proper nutrition; supplement may be needed because of inadequate dietary intake

Food sources of copper; effects of processing

Recommended daily intake for copper

Before using this dietary supplement
»   Conditions affecting use, especially:
Other medications or dietary supplements, especially penicillamine, trientine, or oral zinc supplements
Other medical problems, especially Wilson's disease and biliary tract disease

Proper use of this dietary supplement

» Proper dosing
Missed dose: No cause for concern because of length of time necessary for depletion; remembering to take as directed

» Proper storage

Precautions while using this dietary supplement
Not taking copper supplements within 2 hours of zinc supplements


General Dosing Information
Because of the infrequency of copper deficiency alone, combinations of several vitamins and/or minerals are commonly administered. Many commercial vitamin/mineral complexes are available.

For parenteral dosage forms only
In most cases, parenteral administration is indicated only when oral administration is not acceptable (for example, in nausea, vomiting, and preoperative and postoperative conditions) or possible (for example, in malabsorption syndromes or following gastric resection).

Diet/Nutrition
Recommended dietary intakes for copper are defined differently worldwide.


For U.S.:
The Recommended Dietary Allowances (RDAs) for vitamins and minerals are determined by the Food and Nutrition Board of the National Research Council and are intended to provide adequate nutrition in most healthy persons under usual environmental stresses. In addition, a different designation may be used by the FDA for food and dietary supplement labeling purposes, as with Daily Value (DV). DVs replace the previous labeling terminology United States Recommended Daily Allowances (USRDAs). {03} {37}



For Canada:
Recommended Nutrient Intakes (RNIs) for vitamins, minerals, and protein are determined by Health and Welfare Canada and provide recommended amounts of a specific nutrient while minimizing the risk of chronic diseases. {38}

There is no RDA or RNI established for copper. The following daily intakes are considered adequate for all individuals: {03}


Infants and children—
Birth to 3 years of age: 0.4 to 1 mg.

4 to 6 years of age: 1 to 1.5 mg.

7 to 10 years of age: 1 to 2 mg.



Adolescent and adult males—
1.5 to 2.5 mg.



Adolescent and adult females—
1.5 to 3 mg.


The best sources of copper include organ meats (especially liver), seafoods, beans, nuts, and whole-grains. {03} {14} {16} Additional copper can come from the interaction of drinking water with copper pipes {03}, copper cookware, {03} and copper-containing fungicides sprayed on agricultural products. The amount of copper in foods may be decreased as a result of prolonged storage in tin cans under acidic conditions. {15}


COPPER GLUCONATE


Oral Dosage Forms

COPPER GLUCONATE TABLETS

Usual adult and adolescent dose
Deficiency (prophylaxis)—Oral, amount based on normal daily recommended intakes: {03} {38}
Adolescent and adult males—1.5 to 2.5 mg.

Adolescent and adult females—1.5 to 3 mg.

Deficiency (treatment)
Treatment dose is individualized by prescriber based on severity of deficiency.


Usual pediatric dose
Deficiency (prophylaxis)—Oral, amount based on normal daily recommended intakes: {03} {38}
Birth to 3 years of age—0.4 to 1 mg.

4 to 6 years of age—1 to 1.5 mg.

7 to 10 years of age—1 to 2 mg.

Deficiency (treatment)
Treatment dose is individualized by prescriber based on severity of deficiency.


Strength(s) usually available
U.S.—


3 mg elemental copper (OTC)[Generic]

Canada—
Not commercially available.

Note: The strength of this preparation may exceed the dosage range recommended by USP DI Advisory Panels based on the amount necessary to meet normal nutritional needs.


Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a tight container.


CUPRIC SULFATE


Parenteral Dosage Forms

Note: Injectable copper products must be diluted prior to intravenous administration.


CUPRIC SULFATE INJECTION USP

Usual adult and adolescent dose
Deficiency (prophylaxis)
Intravenous infusion, 0.5 to 1.5 mg of elemental copper a day added to TPN. {01}

Deficiency (treatment)
Intravenous infusion, 3 mg of elemental copper a day added to total parenteral nutrition (TPN). {33}


Usual pediatric dose
Deficiency (prophylaxis)—For full-term infants and children:
Intravenous infusion, 20 mcg elemental copper per kg of body weight per day added to TPN. {01}

Deficiency (treatment)—For full-term infants and children:
Intravenous infusion, 20 to 30 mcg elemental copper per kg of body weight per day added to TPN. {34}


Note: Copper injection that contains benzyl alcohol as a preservative should not be used in newborn and immature infants. The use of benzyl alcohol in neonates has been associated with a fatal toxic syndrome consisting of metabolic acidosis and CNS, respiratory, circulatory, and renal function impairment.


Strength(s) usually available
U.S.—


0.4 mg elemental copper per mL (1.57 mg cupric sulfate) (Rx) [Cupri-Pak][Generic]


2 mg elemental copper per mL (7.85 mg cupric sulfate) (Rx)[Generic]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Preparation of dosage form:
The manufacturer states that copper sulfate can be added to TPN solutions, and is physically compatible with amino acid solutions, dextrose solutions, and most vitamins with the exception of ascorbic acid. {07}

Incompatibilities:
Large doses of ascorbic acid are physically incompatible with copper. {01} {05} The manufacturer recommends that copper sulfate and other trace metal additives be added to TPN solutions immediately prior to infusion to avoid potential incompatibilities. {01}



Revised: 05/26/95



References
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Further information

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