Prescription Drugs

CLINICAL PHARMACOLOGY Zinc is an essential nutritional requirement that serves as a cofactor for more than 70 different enzymes including carbonic anhydrase alkaline phosphatase, lactic dehydrogenase,and both RNA and DNA polymerase. Zinc facilitates wound healing, helps maintain normal skin hydration and the senses of taste and smell. Zinc resides in muscle, bone, skin, the kidney, liver, pancreas, retina, prostate and particularly in the red and white blood cells. Zinc binds to plasma albumin, a2-macroglobulin and some plasma amino acids including histidine, cysteine, threonine, glycine and asparagine. Ingested zinc is excreted mainly in the stool (approximately 90%), and to a lesser extent in the urine and in perspiration. Providing zinc during TPN helps prevent development of deficiency symptoms such as: Parakeratosis, hypogeusia, anorexia, dysosmia, geophagia,hypogonadism, growth retardation and hepatosplenomegaly. The initial manifestations of hypozincemia in TPN patients are diarrhea, apathy and depression. At plasma levels below 20 mcg zinc/100 mL, dermatitis followed by alopecia has been reported for TPN patients. Normal zinc plasma levels are 100±12 mcg/100 mL. Copper is an essential nutrient that serves as a cofactor for serum ceruloplasmin, an oxidase necessary for proper formation of the iron carrier protein, transferrin. Providing copper during TPN helps prevent development of the following deficiency symptoms: Leukopenia,neutropenia, anemia, depressed ceruloplasmin levels, impaired transferrin formation and secondary iron deficiency. Normal serum copper values range from 80 to 163 mcg/100 mL (mean, approximately 110 mcg/100 mL). The serum copper level at which deficiency symptoms appear is not precisely defined. The daily turnover of copper through ceruloplasmin is approximately 0.5 mg. Excretion of copper is through the bile (80%), directly through the intestinal wall (16%), and in urine (4%). Manganese is an essential nutrient that serves as an activator for enzymes such as polysaccharide polymerase, liver arginase, cholinesterase and pyruvate carboxylase. Providing manganese during TPN helps prevent development of deficiency symptoms such as nausea and vomiting, weight loss, dermatitis and changes in growth and color of hair. Under conditions of minimal intake, 20 mcg manganese/day is retained. Manganese is bound to a specific transport protein, transmanganin, a p31-globulin. Manganese is widely distributed but concentrates in the mitochondria-rich tissues such as brain, kidney, pancreas and liver. Assay for manganese in whole blood results in concentrations ranging from 6 to 12 mcg manganese/L. Excretion of manganese occurs mainly through the bile, but in the event of obstruction, ancillary excretion routes include pancreatic juice, or return into the lumen of duodenum, jejunum or ileum. Urinary excretion of manganese is negligible. Trivalent chromium is party of glucose tolerance factor, an essential activator of insulin-mediated reactions. Chromium helps to maintain normal glucose metabolism and peripheral nerve function. Providing chromium during TPN helps prevent deficiency symptoms including impaired glucose tolerance, ataxia, peripheral neuropathy and a confusional state similar to mild/moderate hepatic encephalopathy. Serum chromium is bound to transferrin (siderophilin) in the b-globulin fraction. Typical blood levels for chromium range from 1 to 5 mcg/L, but blood levels are not considered a meaningful index of tissue stores. Administration of chromium supplements to chromium-deficient patients can result in normalization of the glucose tolerance curve from the diabetic-like curve typical of chromium deficiency. This response is viewed as a more meaningful indicator of chromium nutriture than serum chromium levels. Excretion of chromium is via the kidneys, ranging from 3 to 50 mcg/day. Biliary excretion via the small intestine may be an ancillary route, but it is believed that only small amounts of chromium are excreted in this manner.

DESCRIPTION Pedtrace (zinc, copper, manganese and chromium intravenous solution) ®-4 is a sterile, nonpyrogenic solution of four trace elements for use as an additive for total parenteral nutrition (TPN) in pediatric patients. Each mL contains: Zinc Sulfate heptahydrate (equivalent to Zinc 0.5 mg) 2.2 mg Cupric Sulfate pentahydrate (equivalent to Copper 0.1 mg) 0.39 mg Manganese Sulfate monohydrate (equivalent to Manganese 25 mcg) 77 mcg Chromic Chloride hexahyd rate (equivalent to Chromium 0.85 mcg) 4.36 mcg Water for Injection q. s. Zinc sulfate is chemically designated ZnSO4, a white crystalline compound freely soluble in water. Cupric sulfate is chemically designated CuSO4, a blue crystalline compound very soluble in water. Manganese sulfate is chemically designated MnSO4, a pale red, slightly efflorescent compound soluble in water. Chromic chloride is chemically designated CrCl3, a greenish compound soluble in water. Sulfuric acid for pH adjustment (approximately 2.5).

INDICATIONS Pedtrace (zinc, copper, manganese and chromium intravenous solution) ®-4 is indicated for use as a supplement to intravenous solution given for TPN. Administration of Pedtrace®-4 in TPN solutions helps to maintain plasma levels of zinc, copper, manganese, and chromium and to prevent depletion of endogenous stores of these trace elements and subsequent deficiency symptoms in pediatric patients. DOSAGE AND ADMINISTRATION The suggested dosage ranges for the four trace elements in neonates and pediatric patients are: ZINC: For full term infants and children up to 5 years of age, 100 mcg zinc/kg/day is recommended. For premature infants up to 3 kg in body weight, 300 mcg zinc/kg/day is suggested. COPPER: For pediatric patients, the suggested additive dosage level is 20 mcg copper/kg/day. MANGANESE: For pediatric patients, a dosage of 2 to 10 mcg manganese/kg/day is suggested. CHROMIUM: For pediatric patients, the suggested additive dosage is 0.14 to 0.20 mcg/kg/day Periodic monitoring of plasma levels of zinc, copper, manganese and chromium is suggested as a guideline preparation. Aseptic addition of Pedtrace®-4 to the TPN solution under a laminar wflow hood is recommended. The trace elements present in Pedtrace (zinc, copper, manganese and chromium intravenous solution) ®-4 are physically compatible with the electrolytes and vitamins usually present in the amino acid/dextrose solution used for TPN. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit. HOW SUPPLIED Product No. NDC No. 13803 0469-1380-03 Pedtrace®-4 in a 3 mL single-dose, flip-top vial in packages of 25. 13810 0469-1380-30 Pedtrace®-4 in a 10 mL single-dose, flip-top vial in packages of 25. Store at controlled room temperature 15°-30°C (59°-86°F). Preservative Free. Discard unused portion. CAUTION: Federal law prohibits dispensing without prescription.

PATIENT INFORMATION See WARNINGS, PRECAUTIONS and CONTRAINDICATIONS.

OVERDOSE Single intravenous doses of 1 to 2 mg zinc/kg body weight have been given to adult leukemic patients without toxic manifestations. However, acute toxicity was reported in an adult when 10 mg zinc was infused over a period of one hour on each of four consecutive days. Profuse sweating, decreased level of consciousness, blurred vision, tachycardia (140/mm) and marked hypothermia (94.2°F) on the fourth day were accompanied by a serum zinc concentration of 207 mcg/mL. Symptoms abated within three hours. Hyperamylasemia may be a sign of impending zinc overdosage; patients receiving an inadvertent overdose (25 mg zinc/L of TPN solution, equivalent to 50 to 70 mg zinc/day) developed hyperamylasemia (557 to 1850 Klein units; normal: 130 to 310). Death resulted from an overdose in which 1683 mg zinc was delivered intravenously over the course of 60 hours to a 72-year-old patient. Symptoms of zinc toxicity included hypotension (80/40 mm Hg), pulmonary edema, diarrhea, vomiting, jaundice and oliguria with a serum zinc level of 4184 mcg/100 mL. Calcium supplements may confer a protective effect against zinc toxicity. Copper toxicity can produce prostration, behavior change, diarrhea, progressive marasmus, hypotonia, photophobia and peripheral edema. Such symptoms have been reported with a serum copper level of 286 mcg/100 mL. D-penicillamine has been reported effective as an antidote. Manganese toxicity in TPN patients has not been reported within the prescribed dosage. Trivalent chromium administered intravenously to TPN patients has been shown to be nontoxic when given at dosage levels of up to 250 mcg/day for two consecutive weeks. Reported toxic reactions to chromium include nausea, vomiting, ulcers of the gastrointestinal tract, renal and hepatic damage, convulsions and coma. The acute LD50 for intravenous trivalent chromium in rats was reported as 10 to 18 mg/kg. CONTRAINDICATIONS Pedtrace (zinc, copper, manganese and chromium intravenous solution) ®-4 should not be given undiluted by direct injection into a peripheral vein because of the potential of infusion phlebitis.

SIDE EFFECTS The amounts of zinc, copper, chromium and manganese in Pedtrace (zinc, copper, manganese and chromium intravenous solution) ®-4 are very small and toxicity symptoms due to these trace elements at suggested dosage levels are considered unlikely to occur. DRUG ABUSE AND DEPENDENCE None known. DRUG INTERACTIONS No information provided.

WARNINGS Pedtrace (zinc, copper, manganese and chromium intravenous solution) ®-4 is a hypotonic solution which should be administered in admixtures only. Supplementation of TPN solutions with Pedtrace (zinc, copper, manganese and chromium intravenous solution) ®-4 should be immediately discontinued if toxicity symptoms due to any of the constituent trace elements in Pedtrace (zinc, copper, manganese and chromium intravenous solution) ®-4 is observed in the patient. PRECAUTIONS † Before administering Pedtrace®-4 in TPN solutions, the physician must assess the metabolic requirements of trace elements and disease state of the patient. Frequent determinations of serum levels of the four trace elements are suggested as a guideline for adjusting the dosage or completely omitting Pedtrace (zinc, copper, manganese and chromium intravenous solution) ®-4. Zinc is eliminated via the intestine and kidneys; copper and manganese are eliminated mainly via the bile; and chromium primarily via the kidneys. The possibility of their retention should be considered in patients with malfunctioning excretory routes of the respective trace elements. † Syringes equipped with aluminum needles or hubs should not be used, as the solution is acidic. Pregnancy Category C Animal reproduction studies have not been conducted with Pedtrace (zinc, copper, manganese and chromium intravenous solution) ®-4. It is also not known whether Pedtrace (zinc, copper, manganese and chromium intravenous solution) ®-4 can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Pedtrace (zinc, copper, manganese and chromium intravenous solution) ®-4 should be given to a pregnant woman only if clearly needed.