ASCORBIC ACID

Ascorbic acid injection, USP for intravenous use is a colorless to pale yellow, preservative-free, hypertonic, sterile, non-pyrogenic solution of ascorbic acid. Ascorbic acid injection must be diluted with an appropriate infusion solution (e.g., 5% Dextrose Injection, USP; Sterile Water for Injection, USP) [see Dosage and Administration (2.1) ] . The chemical name of ascorbic acid, USP is L -ascorbic acid. The molecular formula is C 6 H 8 O 6 . It has the following structural formula: Each ascorbic acid injection, USP, 50 mL, Pharmacy Bulk Package vial that contains 25,000 mg ascorbic acid, equivalent to 28,125 mg sodium ascorbate. Each mL of ascorbic acid injection, USP contains 500 mg of ascorbic acid (equivalent to 562.5 mg of sodium ascorbate which amounts to 65 mg sodium/mL of ascorbic acid injection), 130 mg of sodium bicarbonate 0.28 mg of edetate disodium (dihydrate). Sodium hydroxide is added for pH adjustment (pH range 5.6 to 6.6). It contains no bacteriostatic or antimicrobial agent. Structural formula of Ascorbic Acid

Ascorbic acid injection is indicated for the short term (up to 1 week) treatment of scurvy in adult and pediatric patients, age 5 months and older, for whom oral administration is not possible, insufficient or contraindicated. Limitations of Use Ascorbic acid injection is not indicated for the treatment of vitamin C deficiency that is not associated with signs and symptoms of scurvy. Ascorbic acid injection is vitamin C indicated for the short term (up to 1 week) treatment of scurvy in adult and pediatric patients age 5 months and older for whom oral administration is not possible, insufficient or contraindicated. Limitations of Use Ascorbic acid injection is not indicated for treatment of vitamin C deficiency that is not associated with signs and symptoms of scurvy.

• Supplied in a Pharmacy Bulk Package (PBP). Dispense single doses to multiple patients in a pharmacy admixture program; use within 4 hours of puncture. ( 2.1 ) • Must be diluted prior to use ( 2.1 ) • Administer as a slow intravenous infusion ( 2.1 ) • See Full Prescribing Information for important administration instructions ( 2.1 ) • Maximum recommended duration is one week ( 2.2 ) Population ( 2.2 ) Recommended Doses Pediatric patients age 5 months to less than 12 months 50 mg once daily Pediatric patients age 1 year to less than 11 years 100 mg once daily Adults and pediatric patients age 11 years and older 200 mg once daily Specific Populations ( 2.3, 8.1, 8.2 ) Pregnant women, lactating women, patients with glucose-6-phosphate dehydrogenase deficiency Should not exceed the U.S. Recommended Dietary Allowance (RDA) 2.1 Important Preparation and Administration Instructions • Ascorbic acid injection vials contain 25,000 mg of ascorbic acid and the largest recommended single dose is 200 mg. Do not give the entire contents of the vial to a single patient. • Do not administer ascorbic acid injection as an undiluted intravenous injection. • Minimize exposure to light because ascorbic acid injection is light sensitive. • Ascorbic acid injection is supplied as a Pharmacy Bulk Package (PBP) which is intended for dispensing of single doses to multiple patients in a pharmacy admixture program and is restricted to the preparation of admixtures for infusion: a. Use only in a suitable ISO Class 5 work area such as a laminar flow hood (or an equivalent clean air compounding area). b. Penetrate each PBP vial closure only one time with a suitable sterile transfer device or dispensing set that allows measured dispensing of the contents. Given that pressure may develop within the vial during storage, exercise caution when withdrawing contents from the vial. c. Once the closure system has been penetrated, complete all dispensing from the PBP vial within 4 hours . Each dose must be used immediately . Discard unused portion. d. Prior to administration , ascorbic acid injection must be diluted in a suitable infusion solution and the final solution for infusion must be isotonic (undiluted the osmolarity of ascorbic acid injection is approximately 5,900 mOsmol/L). Prior to preparing the admixture for infusion, calculate the osmolarity of the intended admixture for infusion. Add one daily dose of ascorbic acid injection directly to an appropriate volume of a suitable infusion solution (e.g., 5% Dextrose Injection, Sterile Water for Injection) and add appropriate solutes, as necessary, to make the final solution isotonic. Sterile Water for Injection is highly hypotonic; adjust solute content, as necessary, to make the final infusion solution isotonic prior to injection. Do not mix ascorbic acid injection with solutions containing elemental compounds that can be reduced (e.g., copper). The concentration of ascorbic acid in the final, admixture solution for infusion is to be in the range of 1 to 25 mg of ascorbic acid per mL. For example, for the largest recommended dose: Add 200 mg of ascorbic acid (equivalent to 0.4 mL of ascorbic acid injection) to 7.5 mL of Sterile Water for Injection to produce an infusion solution having an approximate osmolarity of 290 mOsmol/L. In this specific example, addition of solute is NOT necessary because the solution is isotonic. e. Prepare the recommended dose based on the patient population [see Dosage and Administration (2.2), (2.3) ]. f. Visually inspect for particulate matter and discoloration prior to administration (the diluted ascorbic acid injection solution should appear colorless to pale yellow). g. Immediately administer the admixture for infusion as a slow intravenous infusion [see Recommended Dosage (2.2) ] 2.2 Recommended Dosage Table 1 provides recommended doses of ascorbic acid injection based on patient population and infusion rates of diluted ascorbic acid injection solution. Table 1: Recommended Dose of ascorbic acid injection and Infusion Rate of Diluted ascorbic acid injection Solution Patient Population Ascorbic acid injection Once Daily Dose (mg) Infusion Rate of Diluted Ascorbic acid injection Solution (mg/minute) Pediatric Patients age 5 months to less than 12 months 50 1.3 Pediatric Patients age 1 year to less than 11 years 100 3.3 Adults and Pediatric Patients 11 years and older 200 33 The recommended maximum duration of daily treatment with ascorbic acid injection is seven days. If no improvement in scorbutic symptoms is observed after one week of treatment, retreat until resolution of scorbutic symptoms is observed. Repeat dosing is not recommended in pediatric patients less than 11 years of age. 2.3 Dosage Reductions in Specific Populations Women who are pregnant or lactating and patients with glucose-6-dehydrogenase deficiency should not exceed the U.S. Recommended Dietary Allowance (RDA) or daily Adequate Intake (AI) level for ascorbic acid for their age group and condition [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.2) ]. 2.1 Important Preparation and Administration Instructions • Ascorbic acid injection vials contain 25,000 mg of ascorbic acid and the largest recommended single dose is 200 mg. Do not give the entire contents of the vial to a single patient. • Do not administer ascorbic acid injection as an undiluted intravenous injection. • Minimize exposure to light because ascorbic acid injection is light sensitive. • Ascorbic acid injection is supplied as a Pharmacy Bulk Package (PBP) which is intended for dispensing of single doses to multiple patients in a pharmacy admixture program and is restricted to the preparation of admixtures for infusion: a. Use only in a suitable ISO Class 5 work area such as a laminar flow hood (or an equivalent clean air compounding area). b. Penetrate each PBP vial closure only one time with a suitable sterile transfer device or dispensing set that allows measured dispensing of the contents. Given that pressure may develop within the vial during storage, exercise caution when withdrawing contents from the vial. c. Once the closure system has been penetrated, complete all dispensing from the PBP vial within 4 hours . Each dose must be used immediately . Discard unused portion. d. Prior to administration , ascorbic acid injection must be diluted in a suitable infusion solution and the final solution for infusion must be isotonic (undiluted the osmolarity of ascorbic acid injection is approximately 5,900 mOsmol/L). Prior to preparing the admixture for infusion, calculate the osmolarity of the intended admixture for infusion. Add one daily dose of ascorbic acid injection directly to an appropriate volume of a suitable infusion solution (e.g., 5% Dextrose Injection, Sterile Water for Injection) and add appropriate solutes, as necessary, to make the final solution isotonic. Sterile Water for Injection is highly hypotonic; adjust solute content, as necessary, to make the final infusion solution isotonic prior to injection. Do not mix ascorbic acid injection with solutions containing elemental compounds that can be reduced (e.g., copper). The concentration of ascorbic acid in the final, admixture solution for infusion is to be in the range of 1 to 25 mg of ascorbic acid per mL. For example, for the largest recommended dose: Add 200 mg of ascorbic acid (equivalent to 0.4 mL of ascorbic acid injection) to 7.5 mL of Sterile Water for Injection to produce an infusion solution having an approximate osmolarity of 290 mOsmol/L. In this specific example, addition of solute is NOT necessary because the solution is isotonic. e. Prepare the recommended dose based on the patient population [see Dosage and Administration (2.2), (2.3) ]. f. Visually inspect for particulate matter and discoloration prior to administration (the diluted ascorbic acid injection solution should appear colorless to pale yellow). g. Immediately administer the admixture for infusion as a slow intravenous infusion [see Recommended Dosage (2.2) ] 2.2 Recommended Dosage Table 1 provides recommended doses of ascorbic acid injection based on patient population and infusion rates of diluted ascorbic acid injection solution. Table 1: Recommended Dose of ascorbic acid injection and Infusion Rate of Diluted ascorbic acid injection Solution Patient Population Ascorbic acid injection Once Daily Dose (mg) Infusion Rate of Diluted Ascorbic acid injection Solution (mg/minute) Pediatric Patients age 5 months to less than 12 months 50 1.3 Pediatric Patients age 1 year to less than 11 years 100 3.3 Adults and Pediatric Patients 11 years and older 200 33 The recommended maximum duration of daily treatment with ascorbic acid injection is seven days. If no improvement in scorbutic symptoms is observed after one week of treatment, retreat until resolution of scorbutic symptoms is observed. Repeat dosing is not recommended in pediatric patients less than 11 years of age. 2.3 Dosage Reductions in Specific Populations Women who are pregnant or lactating and patients with glucose-6-dehydrogenase deficiency should not exceed the U.S. Recommended Dietary Allowance (RDA) or daily Adequate Intake (AI) level for ascorbic acid for their age group and condition [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.2) ].

None. None.

The following adverse reactions are discussed in greater detail in other sections of the labeling: • Oxalate nephropathy and Nephrolithiasis [see Warnings and Precautions (5.1) ]. • Hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency [see Warnings and Precautions (5.2) ]. The following adverse reactions associated with the use of ascorbic acid were identified in the literature. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure: Administration site reactions: pain and swelling. Ascorbic acid injection should not be rapidly administered. Rapid intravenous administration (>250 mg/minute) of ascorbic acid injection may cause temporary faintness or nausea, lethargy, flushing, dizziness, and headache (the recommended infusion rates of diluted ascorbic acid injection solution are 1.3 mg/minute (Pediatric Patients age 5 months to less than 12 months), 3.3 mg/minute (Pediatric Patients age 1 year to less than 11 years) and 33 mg/minute (Adults and Pediatric Patients 11 years and older) [see Dosage and Administration (2.2) ]). Acute and chronic oxalate nephropathy have occurred with prolonged administration of high doses of ascorbic acid [see Warnings and Precautions (5.1) ]. In patients with glucose-6-phosphate dehydrogenase deficiency, severe hemolysis has occurred [see Warnings and Precautions (5.2) ]. Most common adverse reactions are pain and swelling at the site of infusion ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact [Fresenius Kabi USA, LLC at 1-800-551-7176] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• Antibiotics: Ascorbic acid may decrease the activities of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin. Bleomycin is inactivated in vitro by ascorbic acid ( 7.1 ). • Amphetamine and Other Drugs Affected by Urine Acidification: Ascorbic acid may cause acidification of the urine and result in decreased amphetamine serum levels and affect excretion and plasma concentrations of other drugs sensitive to urine pH ( 7.2 ). • Warfarin: Continue standard monitoring ( 7.3 ). 7.1 Antibiotics Ascorbic acid may decrease activities of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin. Bleomycin is inactivated in vitro by ascorbic acid. If the antibiotic efficacy is suspected to be decreased by concomitant administration of ascorbic acid injection, discontinue ascorbic acid injection administration. 7.2 Amphetamines & Other Drugs Affected by Urine Acidification Ascorbic acid may acidify the urine and lower serum concentrations of amphetamine by increasing renal excretion (as reflected by changes in amphetamine urine recovery rates). In case of decreased amphetamine efficacy, discontinue ascorbic acid injection administration. Standard monitoring of therapy is warranted. In addition, acidification of urine by ascorbic acid will alter the excretion of certain drugs affected by the pH of the urine (e.g., fluphenazine) when administered concurrently. It has been reported that concurrent administration of ascorbic acid and fluphenazine has resulted in decreased fluphenazine plasma concentrations. Standard monitoring of therapy is warranted. 7.3 Warfarin Limited case reports have suggested interference of ascorbic acid with the anticoagulation effects of warfarin; however, for patients on warfarin therapy treated with ascorbic acid doses up to 1000 mg/day (5 times the largest recommended single dose) for 2 weeks (twice the maximum recommended duration), no effect was observed. Standard monitoring for anti-coagulation therapy should continue during ascorbic acid treatment, as per standard of care. 7.4 Laboratory Test Interference Because ascorbic acid is a strong reducing agent, it can interfere with numerous laboratory tests based on oxidation-reduction reactions (e.g., glucose, nitrite and bilirubin levels, leukocyte count, etc.). Chemical detecting methods based on colorimetric reactions are generally those tests affected. Ascorbic acid may lead to inaccurate results (false negatives) obtained for checking blood or urinary glucose levels, nitrite, bilirubin, and leukocytes if tested during or within 24 hours after infusion [see Warnings and Precautions (5.3) ]. 7.1 Antibiotics Ascorbic acid may decrease activities of erythromycin, kanamycin, streptomycin, doxycycline, and lincomycin. Bleomycin is inactivated in vitro by ascorbic acid. If the antibiotic efficacy is suspected to be decreased by concomitant administration of ascorbic acid injection, discontinue ascorbic acid injection administration. 7.2 Amphetamines & Other Drugs Affected by Urine Acidification Ascorbic acid may acidify the urine and lower serum concentrations of amphetamine by increasing renal excretion (as reflected by changes in amphetamine urine recovery rates). In case of decreased amphetamine efficacy, discontinue ascorbic acid injection administration. Standard monitoring of therapy is warranted. In addition, acidification of urine by ascorbic acid will alter the excretion of certain drugs affected by the pH of the urine (e.g., fluphenazine) when administered concurrently. It has been reported that concurrent administration of ascorbic acid and fluphenazine has resulted in decreased fluphenazine plasma concentrations. Standard monitoring of therapy is warranted. 7.3 Warfarin Limited case reports have suggested interference of ascorbic acid with the anticoagulation effects of warfarin; however, for patients on warfarin therapy treated with ascorbic acid doses up to 1000 mg/day (5 times the largest recommended single dose) for 2 weeks (twice the maximum recommended duration), no effect was observed. Standard monitoring for anti-coagulation therapy should continue during ascorbic acid treatment, as per standard of care. 7.4 Laboratory Test Interference Because ascorbic acid is a strong reducing agent, it can interfere with numerous laboratory tests based on oxidation-reduction reactions (e.g., glucose, nitrite and bilirubin levels, leukocyte count, etc.). Chemical detecting methods based on colorimetric reactions are generally those tests affected. Ascorbic acid may lead to inaccurate results (false negatives) obtained for checking blood or urinary glucose levels, nitrite, bilirubin, and leukocytes if tested during or within 24 hours after infusion [see Warnings and Precautions (5.3) ].