Product Monograph - Micro+ Te Pediatric
RECENT MAJOR LABEL CHANGES
TABLE OF CONTENTS
RECENT MAJOR LABEL CHANGES ............................................................................ 2
TABLE OF CONTENTS .................................................................................................. 2
PART I: HEALTH PROFESSIONAL INFORMATION .................................................... 3
1 INDICATIONS ...................................................................................................... 3
1.1 Pediatrics ................................................................................................... 3
1.2 Geriatrics .................................................................................................... 3
2 CONTRAINDICATIONS ....................................................................................... 3
3 DOSAGE AND ADMINISTRATION ..................................................................... 3
3.1 Recommended Dose and Dosage Adjustment ............................................ 3
3.2 Dilution for intravenous use ......................................................................... 4
3.3 Administration .............................................................................................. 5
4 OVERDOSAGE .................................................................................................... 6
5 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............. 7
6 WARNINGS AND PRECAUTIONS ...................................................................... 8
6.1 Special populations ...................................................................................... 9
6.1.1 Pregnant and/or breastfeeding women ........................................................ 9
6.1.2 Geriatrics ................................................................................................... 10
7 ADVERSE REACTIONS .................................................................................... 10
8 DRUG-FOOD INTERACTIONS .......................................................................... 10
8.1 Drug-Drug Interactions ........................................................................... 10
8.2 Drug-food Interactions ............................................................................ 10
8.3 Drug-Herb Interactions ............................................................................ 10
8.4 Drug-Laboratory Test Interactions ......................................................... 11
9 ACTION AND CLINICAL PHARMACOLOGY ................................................... 11
10 STORAGE, STABILITY AND DISPOSAL ......................................................... 15
11 SPECIAL HANDLING INSTRUCTIONS ............................................................ 16
PART II: SCIENTIFIC INFORMATION ......................................................................... 17
1 PHARMACEUTICAL INFORMATION ............................................................... 17
PATIENT MEDICATION INFORMATION ............................ Error! Bookmark not defined.
PART I: HEALTH PROFESSIONAL INFORMATION
1 INDICATIONS
Micro+® TE Pediatric (5 trace elements) is indicated for use as a pediatric supplement to intravenous solutions given for Total Parenteral Nutrition (TPN) for patients requiring supplementation with all five trace elements. Its administration in TPN solutions helps to maintain plasma zinc, copper, manganese, selenium and iodide levels in theses patients when oral or enteral nutrition is not possible.
Micro+® TE Pediatric helps to prevent depletion of endogenous stores of these 5 trace elements and the development of subsequent deficiency symptoms.
1.1 Pediatrics
Based on the data submitted and reviewed by Health Canada, Micro+® TE Pediatric is authorized for use in pediatric patients. See DOSAGE and ADMINISTRATION.
1.2 Geriatrics
No studies were conducted with Micro+® TE Pediatric in the geriatric population.
Due to the increase frequency of decreased hepatic, renal or cardiac function and the use of concomitant medication, use in the geriatric population may be associated with differences in safety or effectiveness.See WARNINGS and PRECAUTIONS.
2 CONTRAINDICATIONS
Micro+® TE Pediatric is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging.
3 DOSAGE AND ADMINISTRATION
3.1 Recommended Dose and Dosage Adjustment
Micro+ TE Pediatric is recommended only for pediatric patients who require supplementation with all five of the individual trace elements (i.e zinc, copper, manganese, selenium and iodine).
Micro+® TE Pediatric is a fixed-combination product. Each ml of Micro+® TE Pediatric provides zinc 250 mcg, copper 20 mcg, manganese 1 mcg, selenium 2 mcg, and iodide 1 mcg.
Dosing for infants and children 20 kg or less: The recommended dose of Micro+ TE Pediatric is 1 ml/kg/day.
The suggested daily requirements of the five (5) trace elements in pediatric patients are listed below.
Zinc
The recommended dose is 250 mcg zinc/kg/day for full-term infants (3 to 10 kg) and 50 mcg zinc/kg/day for children (10 to 40kg), up to a maximum of 5000 mcg zinc/day.
For preterm infants ( less than 3 kg): 400 mcg zinc/kg/day is recommended. Additional supplementation would be required to meet guideline recommendations. Patients should be monitored for zinc levels, and if needed, they should be supplemented with zinc from another source. Micro+ TE Pediatric should not be used for this additional supplementation.
For children over 20 kg:
At a dose of 1 ml/kg/day of Micro+ TE Pediatric, the dose of zinc would be over the recommended daily maximum requirements. Micro+ TE Pediatric is only recommended to meet the higher needs associated with excessive gastrointestinal losses, sepsis, hypercatabolic states and burns, which require additional supplementation
Copper
The recommended daily dose is 20 mcg/kg/day for all children (less than 40 kg).
Manganese
A dosage level of 1 mcg/kg/day with a maximum daily total dose of 15 mcg of manganese is recommended.
Selenium
The recommended daily dose is 2 mcg/kg/day for all children (less than 40 kg)
Iodine
Iodine is not recommended for routine daily dosing; Micro + TE Pediatric should only be used as per the Healthcare professional assessment of the patient’s iodine needs.
3.2 Dilution for intravenous use
Micro+® TE Pediatric should be aseptically added to the amino acid/dextrose component of a TPN solution under a laminar flow hood. Micro+ TE Pediatric may only be added to medications and parenteral nutrition solutions for which compatibility has been shown.
Micro+® TE Pediatric is used as an additive to parenteral nutrition admixtures in compounded bags where data are available. Compatibility data are available for the addition of Micro+ TE Pediatric to parenteral nutrition products such as 0.9% Sodium chloride (NaCl), 10% dextrose, 10% Travasol® Amino Acid and 20% Intralipid®.
Micro+® TE Pediatric (5 trace elements for injection) can also be co-administered with Infuvite® and Multi-12 drug products when diluted in 0.9% NaCl or 10% Dextrose.
Micro+® TE Pediatric (5 trace elements for injection) can also be co-administered with Magnesium sulfate (50%, USP) when diluted in 10% Dextrose.
Data also demonstrates that Micro+ TE Pediatric can be co-administered with Potassium Phosphates Injection when diluted in 0.9% Sodium chloride (NaCl), 10% dextrose, 10% Travasol® Amino Acid or 20% Intralipid®
After dilution, the solution must be used within 24 hours if store at room temperature or 48 hours if refrigerated (5 ± 3ºC).
Visually inspect parenteral drug products for particulate matter and discolouration prior to and after admixing and before administration whenever container and solution permit. See Storage, stability and Disposal.
The vial is a single use vial. Discard unused portion of the solution.
3.3 Administration
Micro+® TE Pediatric must be diluted before use.
Micro+ TE Pediatric is recommended only for pediatric patients who require supplementation with all five of the individual trace elements (i.e., zinc, copper, manganese, selenium and iodine).
Micro+ TE Pediatric is not recommended for patients who would require a lower dosage of one or more the individual trace elements (i.e. zinc, copper, manganese, selenium or iodide).
Routine monitoring of zinc, copper, manganese, selenium and iodine plasma levels is suggested as a guideline for administration. For iodine, routine monitoring of thyroid function is also suggested.
Zinc
Normal plasma levels vary from approximately 68 to 136 mcg per 100 mL. Frequently monitor the blood zinc levels for those patients receiving more than the usual maintenance dosage level of zinc. The dose in 1 mL of Micro+ TE Pediatric is below the recommended daily dose of zinc for preterm infants weighing 3 kg or less. The patients should be monitored for zinc level, and if needed, they should be supplemented with zinc from another source than Micro+ TE Pediatric
Copper
While the normal adult plasma levels range from 90 to 130 mcg/100 mL, the normal full-term newborn’s serum levels are about one-third of this. These values were found to rise gradually during the first week of life, fall to below adult levels at two months of age, rise to within the adult range at three months of age, and to rise still higher above the adult range at eight months of age, at which levels the values persisted throughout the remainder of infancy.
Manganese
Manganese is bound in both the serum and the erythrocytes. Normal human blood values have been recognized as 6 to 10 mcg/mL.
Selenium
The range for selenium blood levels has been reported as 78 to 157 ng/mL of plasma, and 70 to 229 ng/mL of whole blood.
Iodine
Serum levels of iodine for healthy subjects are 0.08 to 0.60 mcg/100 mL. Thyroid function is a more realistic indicator of iodine requirements, with the protein-bound iodine (PBI) or butanol extractable iodine (BEI) of the serum corresponding reasonably well with the level of thyroid activity; limits of normality have been placed at 3-8 mcg/100 mL of serum. Iodine is not recommended for routine daily dosing in pediatric patients above 3 kg. Micro+ TE Pediatric should only be used as per the Healthcare professional assessment of the patient’s iodine needs.
4 OVERDOSAGE
Zinc
Zinc is a relatively nontoxic compound but toxicity can occur by oral administration, inhalation and hemodialysis. Ingestion of excess zinc has usually resulted from storage of food or beverages in galvanized containers which results in diarrhea, vomiting and fever. One report of intoxication following inhalation of zinc oxide fumes causing fever, headache and vomiting has been reported in the literature. In 1972, a case of zinc poisoning was reported in a patient on hemodialysis with zinc-contaminated water. The patient developed nausea, vomiting, fever and severe anemia.
Infusions of 40 to 80 mg/day of zinc have been used with no apparent ill effects. No adverse effects were reported when a group of 22 patients received a 20 mg infusion before and after surgery. One case of ill effects was reported when a daily 10 mg dose of zinc was infused over one hour for 5 days. The ill effects were tachycardia, hypothermia, profuse sweating and blurred vision.
One death resulted from an overdose of intravenous zinc which was due to a local prescribing error. A 72 year old woman with a high output enterocutaneous fistula inadvertently received a 46 mmol (7.4 g) of zinc sulfate infused over a 60-hour period. Analysis of her serum zinc showed a zinc level of 4184 mcg/100 mL. Clinical manifestations were edema, jaundice, vomiting, diarrhea and oliguria.
Seven patients who received an accidental overdosage (25 mg zinc/litre TPN solution; equivalent to 50 to 70 mg zinc/day) exhibited hyperamylasemia (557 to 1850 Klein Units; normal 130 to 310).
Copper
Ingestion of excess copper due to the storage of food or beverages in copper or brass vessels, and beverage vending machines has resulted in acute gastrointestinal illness. Adverse reactions experienced following the ingestion of large doses of copper sulfate (1 to 50 g) include nausea, vomiting, metallic taste, burning sensation in the œsophagus and stomach, colic, bloody diarrhea, convulsions, hypotension and coma, renal damage with acute kidney necrosis, jaundice associated with liver injury and hæmolysis, anuria/oliguria, and hemolytic anemia.
Symptoms of copper toxicity that have been reported include prostration, behavior change, diarrhea, progressive marasmus, hypotonia, photophobia and peripheral edema.
D-penicillamine has been reported effective as an antidote.
Manganese
Excess of manganese can lead to deposition in the basal ganglia of the brain, which can be demonstrated on magnetic resonance imaging (MRI) and can manifest symptomatically as Parkinson-like signs and symptoms in addition to other neuropsychiatric symptoms. A metal fume fever syndrome can occur after exposure to high concentrations of manganese oxide; a few cases of pneumonitis have been associated with manganese exposure.
Selenium
Chronic selenium toxicity due to occupation related exposure, high selenium content in food, water or oral supplements resembles arsenic toxicity. Hair loss, white horizontal streaking on fingernails, paronychia, fatigue, irritability, hyperreflexia, nausea, vomiting, garlic odour on breath, and metallic taste characterize toxicity. Muscle tenderness, tremor, lightheadedness, and facial flushing are observed in selenite poisoning. Serum selenium levels are elevated but do not correlate well with symptoms. Blood chemistries, hematology, and liver and renal function tests are usually normal.
Acute selenious acid ingestions are almost invariably fatal. Stupor, respiratory depression, hypotension, and death can result several hours post ingestion. Severe hypotension develops secondary both to decreased contractility from a toxic cardiomyopathy and to inappropriately low peripheral vascular resistance. Laboratory abnormalities include thrombocytopenia, moderate hepatorenal dysfunction, and elevated serum creatine kinase levels. The electrocardiogram may demonstrate ST elevations and T wave changes characteristic of myocardial infarction. The urinary excretion of selenium is rapid. Terminal respiratory failure developed after a selenious acid ingestion (15 mL gun bluing solution) despite the use of an extracorporeal membrane oxygenator. Death occurred on the 18th hospital day. The plasma selenium level reached 285 mcg/mL on the first hospital day and returned to normal levels by day 4.
There are no antidotes to selenious acid toxicity; treatment is expectant (cardiopulmonary monitoring in an intensive care setting) and supportive (intravenous infusion, supplemental oxygen and ventilation as needed).
Iodine
The symptoms of acute poisoning from ingestion of iodine are mainly due to its corrosive effects on the gastrointestinal tract: a disagreeable metallic taste, vomiting, abdominal pain, and diarrhea occur. Anuria may occur 1 to 3 days later; death may result from circulatory failure, edema of the glottis resulting in asphyxia, aspiration pneumonia, or pulmonary œdema. Œsophageal stricture may occur if the patient survives the acute stage. The fatal dose is usually 2 or 3 g.
Acute iodine poisoning should be treated with abundant fluids and electrolyte. The symptoms of iodism disappear soon after administration of the drug is discontinued.
| For management of a suspected drug overdose, contact your regional poison control centre. |
|---|
5 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
Table – Dosage Forms, Strengths, Composition and Packaging.
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
Micro+ TE Pediatric (5 Trace Elements for Injection) is a clear, colorless to lightly blueish, sterile liquid, essentially free from visible particles. It is a multi-element solution of 5 trace elements for use as an additive for Total Parenteral Nutrition (TPN).
The osmolarity of the solution is 17-19 mOsm/kg.
PACKAGING
Micro+ TE Pediatric (5 Trace Elements for Injection) is supplied sterile, as 10 mL preservative free single use amber glass vials, boxes of 10.
The stopper is not made with natural rubber latex.
6 WARNINGS AND PRECAUTIONS
Micro+ TE Pediatric is recommended only for pediatric patients who require supplementation with all five of the individual trace elements (i.e zinc, copper, manganese, selenium, and iodine).
New guidelines do not recommend inclusion of iodine in trace elements solutions for pediatric patients weighing more than 3 kg. Therefore, Micro+ TE Pediatric should only be used in cases of demonstrated iodine deficiency.
Micro+ TE Pediatric is not recommended for patients who would require a lower dosage of one or more the individual trace elements (i.e. zinc, copper, manganese, selenium or iodide).
Micro+ TE Pediatric is a hypotonic solution which should be administered in admixtures only.
If toxicity symptoms occur due to any one of the trace elements in Micro+ TE Pediatric, discontinue supplementation of TPN solutions immediately.
Do not give undiluted Micro+ TE Pediatric by direct injection into a peripheral vein because of the potential of infusion phlebitis.
Occasional sensitization to iodine can result in anaphylactic shock. Patients should be evaluated for sensitivity to iodine before administration of Micro+ TE Pediatric.
Excess of manganese can lead to deposition in the basal ganglia of the brain and cause toxic
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
| Intravenous | Concentrate, Sterile solution for intravenous infusion / Zinc 250 mcg/mL Copper 20 mcg/mL Selenium 2 mcg/mL Iodide 1 mcg/mL Manganese 1 mcg/mL | Sulfuric acid and water for injection |
events that manifest symptomatically as Parkinson-like signs and symptoms in addition to other neuropsychiatric symptoms. Accumulation of manganese in the brain can occur with long-term administration when doses higher than the recommended 1 mcg/kg/day are used. Do not supplement the proposed drug product with additional manganese.
Gastrointestinal
The possibility of selenium retention should be considered in patients with renal dysfunction and/or gastrointestinal malfunction since selenium is eliminated in the urine and to a smaller extent in the feces.
Hepatic/Biliary/Pancreatic
The possibility of copper and manganese retention should be a consideration in patients with biliary obstruction and caution should be exercised since copper and manganese are eliminated via the bile. Manganese and copper blood levels and liver function should be monitored regularly (monthly) in such patients. Micro+ TE Pediatric should be stopped if manganese and copper levels rise to the potentially toxic range.
Administration of copper to patients with cholestasis and or cirrhosis may cause accumulation hepatic of copper. Administration of copper to patients with Wilson disease (defect in the metabolism of copper transport) may cause both increased hepatic accumulation of copper and aggravation of the hepatocellular degeneration.
If the patient develops any signs or symptoms of hepatobiliary disease during administration of Micro+ TE Pediatric, verify the serum concentration of copper and ceruloplasmin as well as the concentration of manganese in whole blood. The use of individual trace element products should be considered in these patients.
Renal
The possibility of zinc retention should be a consideration in patients with renal dysfunction and caution should be exercised since zinc is excreted via the kidneys.
The possibility of selenium retention should be considered in patients with renal dysfunction and/or gastrointestinal malfunction since selenium is eliminated in the urine and to a smaller extent in the feces.
Because iodide is mostly eliminated in the urine, iodine may accumulate to toxic levels in patients with renal dysfunction. Consideration should be given to other sources of iodine, such as topical disinfectants or coastal air, as iodine is absorbed through the skin and mucous membranes.
6.1 Special populations
6.1.1 Pregnant and/or breastfeeding women
Micro+ TE Pediatric is intended for use in children.
Animal reproduction studies or clinical investigations during pregnancy have not been carried out with Micro+ TE Pediatric.
The Healthcare professionals should carefully consider the potential risks and benefits of each patient before prescribing this product.
6.1.2 Geriatrics
Micro+ TE Pediatric is intended for use in children.
The Healthcare professionals should carefully consider the potential risks and benefits of each patient before prescribing this product.
7 ADVERSE REACTIONS
No adverse reactions have been reported for the amount of zinc, copper, manganese or selenium present in this product. The amounts are small and toxicity symptoms are not likely to occur at the suggested dosage level. However, adverse reactions have been reported for iodine.
Iodine and iodides can produce goitre and hypothyroidism as well as hyperthyroidism. Goiter and hypothyroidism have also occurred in infants born to mothers who had taken iodides during pregnancy.
Iodine can give rise to allergic reactions which may include urticaria, angioedema, cutaneous hæmorrhage or purpuras, fever, arthralgia, lymphadenopathy, and eosinophilia.
Prolonged administration may lead to iodism, although some of the effects could be considered to be due to hypersensitivity. These include adverse effects on the mouth such as metallic taste, increased salivation, burning or pain, and coryza; there may be swelling and inflammation of the throat. Eyes may be irritated and swollen. Pulmonary œdema may develop. Skin reactions include acneform or severe eruptions (iododerma). Other reported effects include gastrointestinal upsets and diarrhea.
Symptomatic treatment may be required for allergic reactions and iodism, although symptoms usually subside rapidly when administration of iodine is discontinued.
8 DRUG-FOOD INTERACTIONS
8.1 Drug-Drug Interactions
Interactions with other drugs have not been established.
8.2 Drug-food Interactions
The drug is administered intravenously; therefore, there is no interaction with food.
8.3 Drug-Herb Interactions
Interactions with herbal products have not been established.
8.4 Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
9 ACTION AND CLINICAL PHARMACOLOGY
Zinc
Zinc is an essential nutritional element that is important in many enzyme systems either as a metalloenzyme or as an enzyme activator. More than 70 different zinc metalloenzymes have been characterized including carbonic anhydrase, alkaline phosphatase, alcohol dehydrogenase, procarboxypeptidase, superoxide dismutase, glyceraldehyde-3-P dehydrogenase and retinene reductase.
A zinc metalloenzyme is also involved in the synthesis of RNA and DNA, making it important in the normal growth and development process. Zinc facilitates wound healing and helps maintain the senses of taste and smell and normal skin hydration.
The distribution of zinc is wide and nonuniform with the highest concentrations found in the eye, prostate, kidney, liver, muscle, bones, teeth (dental enamel), hair, nails and skin. Zinc is also present in the blood with 75-88% of the total zinc of normal human blood in the red cells, 12-22% in the plasma and 3% in the leukocytes. Normal zinc levels are 8.8 mcg/mL in whole blood, 1.21 mcg/mL in plasma, and 14.4 mcg/mL in erythrocytes.
In a study with 99 healthy young men, a mean serum zinc concentration of
102 mcg/100 mL (range 68-136) was reported. Thirty to forty percent of plasma zinc is bound to alpha 2-macroglobulin and sixty to seventy percent is loosely bound to albumin.
Profound changes in zinc blood levels are seen in various disease states and under stress conditions. Subnormal plasma zinc levels have been reported in patients with malignant tumours, atherosclerosis, postalcoholic cirrhosis of the liver and other liver diseases, tuberculosis and after acute tissue injury, regardless of origin.
Zinc is absorbed primarily from the small intestine. The main route of zinc excretion is in the feces, which contains the total endogenously excreted zinc (pancreatic and intestinal secretions) and zinc not absorbed from the diet. Small amounts of zinc are lost in urine (0.3 to 0.6 mg/day). However accumulative zincuria has been observed following major operations, severe burns, nephrosis, postalcoholic hepatic cirrhosis, hepatic porphyria and starvation. Zinc is also lost through sweat, in hair and sloughing skin.
In patients with gastrointestinal disease receiving total parenteral nutrition (TPN), abnormal zinc excretion occurred from the gastrointestinal tract in diarrheal stools and intestinal fluid lost through suction and fistulous discharge.
Zinc deficiency occurs during long term TPN and, in some cases, during short term TPN, particularly in patients with long-standing enteropathies. TPN patients with zinc deficiency are characteristically apathetic, depressed, and develop diarrhea, alopecia, and a moist eczematous rash in the nasolabial fold, followed by bullous or pustular lesions on other parts of the face, in the groin, and on the hands and feet. These conditions are reversed or relieved by zinc administration. All or some of these zinc deficiency symptoms have been reported in adults, children and premature infants, the most predominant clinical manifestations reported being skin lesions and diarrhea resembling symptoms of acrodermatitis enteropathica.
Plasma zinc levels also declined in premature infants maintained on TPN without supplementation. During the last 10 to 12 weeks of pregnancy, two-thirds of the infant’s zinc stores are transferred from the mother. This patient population is at high risk of developing zinc deficiency because they are born with low body stores, need zinc for growth and may be in negative zinc balance up to 60 days after birth.
Therefore, providing zinc during TPN prevents development of the following deficiency symptoms; parakeratosis, hypogeusia, anorexia, dysosmia, geophagia, hypogonadism, growth retardation and hepatosplenomegaly.
Copper
Copper is an essential nutritional element that is important in many enzyme systems either as a metalloenzyme or an enzyme activator such as: cytochrome-c-oxidase, dopamine-β-hydroxylase, monamine oxidase, superoxide dismutase, tyrosinase, urate oxidase, ceruloplasmin, ferroxidases and metallothionine.
The clinical importance of copper is related to the development and maintenance of collagen protein cross-linkage, structure and function of the central nervous system, iron metabolism, erythropoiesis and pigmentation.
In man, the highest concentrations of copper are found in the liver and brain. Copper is absorbed primarily from the stomach and jejunum; however the exact mechanism of absorption is not clear.
Normal serum plasma levels range from 90 to 130 mcg/100 mL (mean, approximately 110 mcg/100 mL).
Absorbed copper is loosely bound to serum albumin and amino acids for transport and exchange with tissues. After reaching the liver, copper is either stored or released for incorporation into erythrocuprein, ceruloplasmin and the numerous copper containing enzymes.
About 60% of the copper in red blood cells is associated with erythrocuprein while the remainder is more loosely bound to protein.
Copper in plasma is present in two main forms of which 90% is firmly bound to ceruloplasmin and a small percentage is loosely bound to albumin. The remainder is bound to amino acids and enzymes.
Age, diet, hormones and pregnancy influence liver and plasma concentrations of copper.
Copper is excreted primarily via the bile (approximately 80%) in the form of a nonabsorbable protein complex with a further 18% via the intestinal wall and 2-3% via urine. Consequently, ingestion of 2-5 mg of copper per day, would result in copper losses of 0.6 to 2 mg per day, with 0.01 to 0.06 mg in urine. Comparatively small amounts are lost through menstruation and in sweat.
Copper deficiency has been recognized in infants on cow’s milk diets and in malnourished infants being rehabilitated on high-calorie low copper diets. Symptoms experienced include anemia, hypoproteinemia, low serum copper and iron levels, neutropenia, diarrhea and “scurvy-like” bone changes.
Adults and children receiving total parenteral nutrition without copper supplementation have shown these same symptoms along with a parallel decline in plasma copper.
Copper supplementation during TPN helps prevent development of the following deficiency symptoms: leukopenia, neutropenia, anemia, depressed ceruloplasmin levels, impaired transferrin formation and secondary iron deficiency.
Manganese
Manganese, an essential nutrient, is a component of several metalloenzymes, pyruvate carboxylase and superoxide dismutase, and a cofactor of a large number of enzyme systems including polymerase, galactotransferase, arginase and cholinesterase.
Dietary manganese is poorly absorbed. It is estimated that the body of a normal 70 kg man contains 12 to 20 mg of manganese. This relatively small amount is widely distributed without notable concentration. However manganese concentration tends to be higher in tissues rich in mitochondria (liver, kidney and pancreas). Reserve manganese stores do not normally occur.
Plasma manganese is bound to a β1 globulin, transferrin. Normal whole blood levels of manganese range from 6 to 10 mcg/L.
Bile is the major route of manganese excretion with the liver apparently maintaining manganese homeostasis. However, when the biliary route is blocked or overloaded, auxiliary routes, pancreatic juices and the walls of duodenum, jejunum and ileum, increase. Urinary excretion, which is negligible, can be increased by the administration of chelating agents.
Manganese deficiency has been demonstrated in numerous animals and in one human subject with vitamin K deficiency whose symptoms included a delayed blood clotting response, mild evanescent dermatitis, reddening of hair and beard, slowed growth of hair, nails and beard, occasional nausea and vomiting, coincident decrease of serum phospholipids and triglycerides, and moderate weight loss.
Administration of manganese helps prevent deficiency symptoms such as nausea and vomiting, weight loss, reduced phospholipid and triglyceride plasma levels, dermatitis and changes in growth and colour of hair.
Selenium
Selenium is an essential component of glutathione peroxidase, which helps prevent oxidative damage to cells by peroxides and free radicals.
Selenium absorption, retention and distribution within the body and the amounts, forms and routes of excretion vary with the chemical forms and amounts of the element ingested and with the dietary levels of other elements such as arsenic and mercury.
Selenium is absorbed from the small intestine and distributed widely to tissues including liver, skin, muscle, kidney, lung, brain, testis, ovary, heart, spleen, thyroid, pancreas, dental enamel and fingernails.
Blood levels have been shown to vary geographically due to selenium levels of soil and food. Reported values of selenium levels in whole blood vary from 150 ng/mL in selenium deficient areas to 3200 ng/mL in a seleniferous zone (in China). Studies in North America have reported whole blood levels of 70 to 229 ng/mL and plasma levels of 78 to 157 ng/mL.
Excretion occurs mainly via the kidneys. However a small amount of the endogenous stores is lost through the feces.
Keshan disease, a cardiomyopathy of children and young women in China is the only clinical condition that has been firmly linked to selenium deficiency. Plasma selenium levels have been shown to decrease during total parenteral nutrition; however symptoms of selenium deficiency are not seen in all TPN patients. Several factors may influence the development of selenium deficiency including geographical location, nutritional and clinical status, excessive Gl losses, age, volume of fluid administered and duration of selenium deficient TPN. Several cases of cardiomyopathy have occurred in patients receiving total parenteral nutrition. Muscle pain and weakness have been reported during total parenteral nutrition and have responded to selenium supplementation.
Selenium supplementation during TPN helps prevent development of the following deficiency symptoms: cardiomyopathy, muscle pain and weakness.
Iodine
Iodine is an essential trace element in the human diet. It is an important factor in cellular oxidation processes and is necessary for the formation of thyroid hormones thyroglobulin, thyroxine and triiodothyronine. The manifestations of iodine deficiency are those of a deficiency of thyroid hormones. Where dietary iodine limits thyroid output, the basal metabolic rate is reversibly lowered.
The hypothalamus secretes the thyrotropin releasing factor, or TRF, a peptide which provokes the secretion of the thyroid stimulating hormone, or TSH. TSH stimulates the thyroid gland to release its hormone and trap iodide. The thyroid hormones in turn inhibit the release of both TRF by the hypothalamus and TSH by the pituitary, thus keeping the plasma level of the thyroid hormones normal.
The fact that the thyroid hormones play an important role in animal metamorphosis, growth and cell differentiation suggests that these hormones have a primary effect on the control of gene expression.
Thyroid hormones and thus iodine are essential for growth during early life. Athyreosis can lead to a type of dwarfism found in severely goitrous areas, and can be treated with iodine administration.
Endemic goiter, when severe, is frequently associated with endemic cretinism, which is characterized by mental retardation, deafness and deaf-mutism, retarded growth, and neurological abnormalities, as well as hypothyroidism.
Thyroid hormones are important for the development of the gonads and secondary sex organs.
Changes in the skin and hair are among the most constant features of iodine deficiency.
Iodine concentrations in human foods vary with the availability of iodine in the soil or with the amount and nature of fertilizers applied. Overall iodine intakes are determined more by the source of foods composing dietaries than by the choice or proportion of different foods, except for those of marine origin, or where there is iodine enrichment such as iodized salt.
Iodine, as inorganic iodide, is absorbed rapidly and almost completely from all levels of the GI tract. Iodinated amino acids are more slowly and less completely absorbed, or are broken down and absorbed as iodide.
The healthy human adult body contains a total of 15-20 mg iodine, of which 70-80% is present in the thyroid gland. The skeletal muscles contain the next largest proportion of total body iodine. Iodine is also present in the pituitary gland, salivary glands, and bile. Iodine in the tissues is present in both inorganic and organically bound forms. The salivary iodine concentration is proportional to the plasma in organic iodine concentration. The protein-bound iodine of the serum (PBI), or the butanol extractable iodine (BEI) of the serum corresponds reasonably well with the level of thyroid activity in man. In adults the normality has been placed at 4-8 or 3-7.5 mcg/100 mL with a mean close to 5-6 mcg/100 mL. Human colostrum has been reported to contain 50-240 mcg/litre, with 40-80 mcg/litre in human milk, once lactation is established.
The iodide pool is replenished continuously, exogenously from the diet, and endogenously from the saliva, the gastric juice, and the breakdown of thyroid hormones. The rate of removal of iodide from the plasma inorganic iodide pool by the thyroid and kidneys is expressed as thyroid and renal clearances. In normal man the total clearance occurs at the rate of about 50 mL/min over all ranges of plasma iodide examined. Thyroid clearance is sensitive to changes in plasma concentrations and varies with the activity of the gland. In normal adults, the thyroid clears 10-20 mL/min.
Iodine is excreted mainly in the urine, with smaller amounts appearing in the feces and sweat. The level of urinary iodine excretion correlates well with plasma iodide concentration and labelled iodine thyroid uptakes. The lower limit of normal urinary levels has been suggested to be 75 mcg/g creatinine for adult man, 50 mcg/g for adolescents, and 32.5 mcg/g for children 5-10 years of age. Most of the hormonal iodine is degraded by the liver and the iodide returned to the body iodide pool, with little appearing in the feces.
During short term total parenteral nutrition, iodine deficiency is unlikely to occur, except perhaps in patients with long-standing enteropathies; however, long term TPN may require supplementation of iodine.
10 STORAGE, STABILITY AND DISPOSAL
Store at room temperature (15°C to 30°C). Protect from light. Protect from freezing
Micro+ TE Pediatric is available in single use vials. Unused portion of the drug should be discarded.
Do not use if the seal or the vial is damaged.
Diluted product is stable for 24 hours after dilution if stored at room temperature (15°C to 30°C) and 48 hours if stored in refrigerated conditions (5 ± 3°C).
As with all parenteral drug products, reconstituted solution and intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit.
Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should not be used.
11 SPECIAL HANDLING INSTRUCTIONS
Not applicable.
PART II: SCIENTIFIC INFORMATION
1 PHARMACEUTICAL INFORMATION
Drug Substance
Proper Name Molecular Molecular
(Chemical Name) Formula Weight
Zinc sulfate ZnSO4.7H2O 287.5
(Zinc sulfate heptahydrate)
Cupric sulfate CuSO4.5H2O 249.68
(Copper sulfate pentahydrate)
Selenious acid H2SeO3 128.97
(Selenium dioxide, monohydrated)
Manganese sulfate MnSO4 H2O 169.01
(Manganese sulfate monohydrate)
Sodium iodide NaI 149.89
(Sodium iodide)
Description
Micro+ TE Pediatric is a sterile multi-element additive of five trace elements for use as an additive for Total Parenteral Nutrition (TPN).
Zinc sulfate is an odourless, colourless, transparent, efflorescent crystal or white crystalline powder with an astringent metallic taste and freely soluble in water.
Copper sulfate occurs as a blue crystal powder. It effloresces slowly in dry air. Its solution is acid to litmus. It is freely soluble in water and in glycerin, very soluble in boiling water and slightly soluble in alcohol.
Manganese sulfate is a pale red, slightly efflorescent crystal or purple odourless powder. It is soluble in water and insoluble in alcohol.
Selenious acid is a colourless or white crystal, efflorescent in dry air and hygroscopic in moist air. It is insoluble in water and in alcohol.
Sodium iodide occurs as colourless, odourless crystals, or white crystalline powder. It is deliquescent in moist air, and develops a brown tint upon decomposition. It is very soluble in water, and freely soluble in alcohol and in glycerin.