Multiple Vitamins

INFUVITE PEDIATRIC is a combination of vitamins indicated for the prevention of vitamin deficiency in pediatric patients up to 11 years of age receiving parenteral nutrition. The physician should not await the development of clinical signs of vitamin deficiency before initiating vitamin therapy. INFUVITE PEDIATRIC is a combination of vitamins indicated for the prevention of vitamin deficiency in pediatric patients up to 11 years of age receiving parenteral nutrition ( 1 )

INFUVITE PEDIATRIC Single Dose is an injection consisting of two single-dose vials labeled Vial 1 (4 mL) and Vial 2 (1 mL). For the vitamin strengths [see Dosage and Administration ( 2.2 ) and Description ( 11 )] . INFUVITE PEDIATRIC Pharmacy Bulk Package is an injection consisting of two vials labeled Vial 1 (40 mL Fill in 50 mL Vial) and Vial 2 (10 mL). The mixed solution (50 mL) will provide thirty-three 1.5 mL single doses, fifteen 3.25 mL single doses or ten 5 mL single doses. For the vitamin strengths [see Dosage and Administration ( 2.2 ) and Description ( 11 )] . Vial 1 (Single Dose and Pharmacy Bulk Package) is supplied as clear, yellow to orange liquid in amber glass vial, closed with a rubber stopper, clear aluminum seal and a blue flip-off. Vial 2 (Single Dose and Pharmacy Bulk Package) is supplied as clear, colorless to pale yellow liquid in amber glass vial closed with a rubber stopper, clear aluminum seal and pink flip-off.

• INFUVITE PEDIATRIC single dose is an injection consisting of two vials labeled Vial 1 (4 mL) and Vial 2 (1 mL) ( 3 )
• INFUVITE PEDIATRIC pharmacy bulk package is an injection consisting of two vials labeled Vial 1 (40 mL fill in 50 mL) and Vial 2 (10 mL) ( 3 )
• See Full Prescribing Information for vitamin strengths ( 11 )

INFUVITE PEDIATRIC is contraindicated in patients who have:

• An existing hypervitaminosis, or
• A history of hypersensitivity to any vitamins or excipients contained in this formulation.
• Hypersensitivity to any of vitamins or excipients ( 4 )
• Existing hypervitaminosis ( 4 )

• Risk of Aluminum Toxicity : For at risk patients (renal failure or those with prolonged therapy), consider periodic monitoring of aluminum levels ( 5.1 )
• Allergic Reactions : To thiamine may occur ( 5.2 )
• Hypervitaminosis A : Patients with renal failure or liver disease may be at higher risk ( 5.3 )
• Decreased Anticoagulant Effect of Warfarin : Monitor INR ( 5.4 , 7.1 )
• Interferes with Megaloblastic Anemia Diagnosis : Avoid during testing for this disorder ( 5.5 )
• Risk of Vitamin Deficiencies or Excesses : Monitor blood vitamin concentrations ( 5.6 )
• False Negative Urine Glucose Tests : Due to vitamin C ( 5.7 )
• Risk of Vitamin E Toxicity : Additional oral and parenteral vitamin E may result in elevated vitamin E blood concentrations in infants ( 5.8 )
• Low Vitamin A Levels : Monitor vitamin A levels ( 5.9 )
• Risk of E-Ferol Syndrome : Due to polysorbates ( 5.10 )

5.1 Aluminum Toxicity INFUVITE PEDIATRIC contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration in pediatric patients with renal impairment. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solution, which contain aluminum. Research indicates that patients with impaired kidney function, including premature neonates 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. To prevent aluminum toxicity periodically monitor aluminum levels with prolonged parenteral administration of INFUVITE PEDIATRIC.

5.2 Allergic Reactions to Thiamine Allergic reactions such as urticaria, shortness of breath, wheezing and angioedema have been reported following intravenous administration of thiamine, which is found in INFUVITE PEDIATRIC. There have been rare reports of anaphylaxis following intravenous doses of thiamine. No fatal anaphylaxis associated with INFUVITE PEDIATRIC has been reported.

5.3 Hypervitaminosis A Hypervitaminosis A, manifested by nausea, vomiting, headache, dizziness, blurred vision has been reported in patients with renal failure receiving 1.5 mg/day retinol and in patients with liver disease. Therefore, supplementation of renal failure patients and patients with liver disease with vitamin A, an ingredient found in INFUVITE PEDIATRIC, should be undertaken with caution [see Use in Specific Populations ( 8.6 and 8.7 )] . Blood levels of Vitamin A should be monitored periodically.

5.4 Decreased Anticoagulant Effect of Warfarin INFUVITE PEDIATRIC contains Vitamin K which may decrease the anticoagulant action of warfarin. In patients who are on warfarin anticoagulant therapy receiving INFUVITE PEDIATRIC monitor blood levels of prothrombin/INR to determine if dose of warfarin needs to be adjusted.

5.5 Interference with Diagnosis of Megaloblastic Anemia INFUVITE PEDIATRIC contains folic acid and cyanocobalamin which can mask serum deficiencies of folic acid and cyanocobalamin in patients with megaloblastic anemia. Avoid the use of INFUVITE PEDIATRICS in patients with suspected or diagnosed megaloblastic anemia prior to blood sampling for the detection of the folic acid and cyanocobalamin deficiencies.

5.6 Potential to Develop Vitamin Deficiencies or Excesses In patients receiving parenteral multivitamins such as with INFUVITE PEDIATRIC, blood vitamin concentrations should be periodically monitored to determine if vitamin deficiencies or excesses are developing. INFUVITE PEDIATRIC may not correct long-standing specific vitamin deficiencies. The administration of additional doses of specific vitamins may be required [see Dosage and Administration ( 2.2 )] .

5.7 Interference with Urine Glucose Testing INFUVITE PEDIATRIC contains vitamin C which is also known as ascorbic acid. Ascorbic acid in the urine may cause false negative urine glucose results.

5.8 Vitamin E Overdose in Infants Receiving Additional Vitamin E Additional vitamin E supplementations of patients receiving INFUVITE PEDIATRIC may result in elevated blood concentrations of vitamin E and potential vitamin E toxicity in infants. Avoid additional oral or parental doses of vitamin E in infants. Daily dose of INFUVITE PEDIATRIC contains adequate concentrations of vitamin E required to achieve normal blood levels of vitamin E.

5.9 Risk of Low Vitamin A Levels Lower vitamin A concentrations may occur after administration of INFUVITE PEDIATRIC due to the adherence of Vitamin A to plastic. Monitor blood vitamin A concentrations periodically. Additional administration of therapeutic doses of vitamin A may be required, especially in low-birth weight infants.

5.10 Risk of E-Ferol Syndrome in Low-Birth Weight Infants E-Ferol syndrome manifested by thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension and metabolic acidosis has been reported in low-birth weight infants following administration of polysorbates which are found in INFUVITE PEDIATRIC. No E-Ferol syndrome associated with INFUVITE PEDIATRIC has been reported.

The following adverse reactions are discussed in greater detail in other sections of the labeling.

• Allergic reactions to thiamine [see Warnings and Precautions ( 5.2 )] .
• Hypervitaminosis A [see Warnings and Precautions ( 5.3 )] The following adverse reactions have been identified during postapproval use of INFUVITE PEDIATRIC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatologic: rash, erythema, pruritis CNS: headache, dizziness, agitation, anxiety Ophthalmic: diplopia Adverse reactions have included anaphylaxis, rash, erythema, pruritis, headache, dizziness, agitation, anxiety, diplopia ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

A number of interactions between vitamins and drugs have been reported. The following are examples of these types of interactions. Effect of INFUVITE PEDIATRIC on other drugs:

• Antibiotics : Thiamine, riboflavin, pyridoxine, niacinamide, and ascorbic acid decrease activities of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin ( 7.1 )
• Bleomycin : Ascorbic acid and riboflavin may reduce the activity of bleomycin ( 7.1 )
• Levodopa : Pyridoxine may decrease blood levels of levodopa and levodopa efficacy may decrease ( 7.1 )
• Phenytoin : Folic acid may decrease phenytoin blood levels and increase risk of seizure activity ( 7.1 )
• Methotrexate : Folic acid may decrease response to methotrexate ( 7.1 ) Effects of other drugs on INFUVITE PEDIATRIC:
• Hydralazine, Isoniazid : Concomitant administration of hydralazine or isoniazid may increase pyridoxine requirements ( 7.2 ).
• Phenytoin : May decrease folic acid concentrations ( 7.2 )

7.1 Drug Interactions Affecting Co-Administered Drugs Warfarin : Vitamin K, a component of INFUVITE PEDIATRIC, antagonizes the anticoagulant action of warfarin. In patients who are co-administered warfarin and INFUVITE PEDIATRIC, blood levels of prothrombin/INR should be monitored to determine if dose of warfarin needs to be adjusted [see Warnings and Precautions ( 5.4 )] . Antibiotics : Thiamine, riboflavin, pyridoxine, niacinamide, and ascorbic acid decrease antibiotic activities of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin. Bleomycin : Ascorbic acid and riboflavin inactivate bleomycin in vitro , thus the activity of bleomycin may be reduced. Levodopa : Pyridoxine may increase the metabolism of levodopa (decrease blood levels of levodopa) and decrease its efficacy. Phenytoin : Folic acid may increase phenytoin metabolism and lower the serum concentration of phenytoin resulting in increased seizure activity. Methotrexate : Folic acid may decrease a patient’s response to methotrexate therapy.

7.2 Drug Interactions Affecting Vitamin Levels Hydralazine, Isoniazid : Concomitant administration of hydralazine or isoniazid may increase pyridoxine requirements. Phenytoin : Phenytoin may decrease serum folic acid concentrations.

• Pregnancy and Lactation : Pregnant and lactating patients should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may exceed those of nonpregnant and nonlactating patients ( 8.1 , 8.2)
• Renal Impairment : Monitor renal function, calcium, phosphorus and vitamin A levels ( 8.6 )
• Hepatic Impairment : Monitor vitamin A levels ( 8.7 )

8.1 Pregnancy Risk Summary Administration of the approved recommended dose of INFUVITE PEDIATRIC in parental nutrition is not expected to cause major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnant patients should follow the U.S. Recommended Daily Allowances for pregnancy because their vitamin requirements may exceed those of nonpregnant patients. Deficiency of essential vitamins may result in adverse pregnancy outcomes (see Clinical Considerations) . Animal reproduction studies have not been conducted with INFUVITE PEDIATRIC. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo-Fetal Risk Deficiency of essential vitamins has been associated with adverse pregnancy and fetal outcomes, such as maternal folic acid deficiency and an increased risk of neural tube defects. Therefore, parenteral nutrition with multiple vitamins injection should be considered if a pregnant patient’s nutritional requirements cannot be fulfilled by oral or enteral intake.

8.2 Lactation Risk Summary Multiple vitamins present in INFUVITE PEDIATRIC are also present in human milk. Administration of the approved recommended dose of Infuvite Pediatric in parental nutrition is not expected to cause harm to a breastfed infant. There is no information on the effects of Infuvite Pediatric on milk production. Lactating patients should follow the U.S. Recommended Daily Allowances for their condition, because their vitamin requirements may exceed those of nonlactating patients. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INFUVITE PEDIATRIC and any potential adverse effects on the breastfed child from INFUVITE PEDIATRIC or from the underlying maternal condition.

8.4 Pediatric Use INFUVITE PEDIATRIC is approved for the prevention of vitamin deficiency in pediatric patients up to 11 years old receiving parenteral nutrition. INFUVITE PEDIATRIC has not been studied in pediatric patients older than 11 years. INFUVITE PEDIATRIC contains aluminum that may be toxic for premature neonates. Aluminum levels should be monitored periodically during administration of INFUVITE PEDIATRIC to premature neonates [see Warnings and Precautions ( 5.1 )] . Additional vitamin E supplementations of infants receiving INFUVITE PEDIATRIC may result in elevated blood concentrations of vitamin E and potential vitamin E toxicity [see Warnings and Precautions ( 5.8 )] . E-Ferol syndrome has been reported in low-birth weight infants following administration of polysorbates which are found in INFUVITE PEDIATRIC. No E-Ferol syndrome associated with INFUVITE PEDIATRIC has been reported [see Warnings and Precautions ( 5.10 )] .

8.6 Renal Impairment INFUVITE PEDIATRIC has not been studied in patients with renal impairment. Monitor renal function, calcium, phosphorus and vitamin A levels in patients with renal impairment [see Warnings and Precautions ( 5.1 and 5.3 )].

8.7 Hepatic Impairment INFUVITE PEDIATRIC has not been studied in patients with liver impairment. Monitor vitamin A levels in patients with liver disease [see Warnings and Precautions ( 5.3 )].