Safety Information

WARNINGS AND PRECAUTIONS

Oxalate Nephropathy and Nephrolithiasis

Acute and chronic oxalate nephropathy have been reported with prolonged administration of high doses of ascorbic acid. Acidification of the urine by ascorbic acid may cause precipitation of cysteine, urate or oxalate stones. Patients with renal disease including renal impairment, history of oxalate kidney stones, and geriatric patients may be at increased risk for oxalate nephropathy while receiving treatment with ascorbic acid. Pediatric patients less than 2 years of age may be at increased risk for oxalate nephropathy during treatment with ascorbic acid because their kidneys are immature. Monitor renal functions in these patients during treatment with ASCOR^®. Discontinue ASCOR^® in patients who develop oxalate nephropathy and treat any suspected oxalate nephropathy.

ASCOR^® is not indicated for prolonged administration (the maximum recommended duration is one week).

Hemolysis in Patients with Glucose-6-Phosphate Dehydrogenase Deficiency

Hemolysis has been reported with administration of ascorbic acid in patients with glucose-6-phosphate dehydrogenase deficiency. Patients with glucose-6-phosphate dehydrogenase deficiency may be at increased risk for severe hemolysis during treatment with ascorbic acid. Monitor hemoglobin and blood count and use a reduced dose of ASCOR^® in patients with glucose-6-phosphate dehydrogenase deficiency. Discontinue treatment with ASCOR^® if hemolysis is suspected and treat as needed.

Laboratory Test Interference

Ascorbic acid may interfere with laboratory tests based on oxidation-reduction reactions, including blood and urine glucose testing, nitrite and bilirubin levels, and leucocyte count testing. If possible, laboratory tests based on oxidation-reduction reactions should be delayed until 24 hours after infusion of ASCOR^®.

ADVERSE REACTIONS

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

• Oxalate nephropathy and Nephrolithiasis [see Warnings and Precautions]
• Hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency [see Warnings and Precautions]

The above 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.

ASCOR^® should not be rapidly administered. Rapid intravenous administration (>250 mg/minute) of ASCOR^® may cause temporary faintness or nausea, lethargy, flushing, dizziness, and headache (the recommended infusion rates of diluted ASCOR^® 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)).

Acute and chronic oxalate nephropathy have occurred with prolonged administration of high doses of ascorbic acid. In patients with glucose-6-phosphate dehydrogenase deficiency severe hemolysis has occurred.

DRUG INTERACTIONS

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 ASCOR^®, discontinue ASCOR^® administration.

Amphetamine & 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 ASCOR^® 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.

Warfarin

Limited case reports have suggested interference of ascorbic acid with the anticoagulation effects of warfarin, however, 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.

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.

USE IN SPECIFIC POPULATIONS

Pregnancy

Risk Summary

There are no available data on the use of ASCOR^® in pregnant women to inform a drug-associated risk of adverse developmental outcomes; however, ascorbic acid (vitamin C) has been used during pregnancy for several decades and no adverse developmental outcomes are reported in the published literature [see Data]. There are dose adjustments for ascorbic acid (vitamin C) use during pregnancy [see Clinical Considerations].

Animal reproduction studies have not been conducted with ASCOR^®.

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

Dose Adjustments During Pregnancy and Post-Partum Period

Follow the U.S. Recommended Dietary Allowances (RDA) for pregnant women when considering use of ASCOR^® for treatment of scurvy [see Dosage and Administration].

Data

Human Data

There are no available data on use of ASCOR^® or another ascorbic acid injection in pregnant women. However, a published meta–analysis of randomized studies evaluating a large number of pregnant women who took oral ascorbic acid (vitamin C) (through diet and supplementation) at doses ranging from 500 to 1000 mg/day (2.5 to 5 times the recommended daily intravenous dose, respectively) [see Dosage and Administration] between the 9th and 16th weeks of pregnancy showed no increased risk of adverse pregnancy outcomes such as miscarriage, preterm premature rupture of membranes, preterm delivery or pregnancy induced hypertension when compared to placebo. These data cannot definitely establish or exclude the absence of a risk with ascorbic acid (vitamin C) during pregnancy.

Lactation

Risk Summary

There are no data on the presence of ascorbic acid (vitamin C) in human milk following intravenous dosing in lactating women. Ascorbic acid (vitamin C) is present in human milk after maternal oral intake. Maternal oral intake of ascorbic acid (vitamin C) exceeding the U.S. Recommended Dietary Allowances (RDA) for lactation does not influence the ascorbic acid (vitamin C) content in breast milk or the estimated daily amount received by breastfed infants. There are no data on the effect of ascorbic acid (vitamin C) on milk production or the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ASCOR^® and any potential adverse effects on the breastfed child from ASCOR or from the underlying maternal condition. Follow the U.S. Recommended Dietary Allowances (RDA) for lactating women when considering use of ASCOR^® for treatment of scurvy [see Dosage and Administration].

Pediatric Use

ASCOR^® is indicated for the short term (up to 1 week) treatment of scurvy in pediatric patients age 5 months and older for whom oral administration is not possible, insufficient or contraindicated. The safety profile of ascorbic acid in pediatric patients is similar to adults; however, pediatric patients less than 2 years of age may be at higher risk of oxalate nephropathy following ascorbic acid administration due to age-related decreased glomerular filtration [see Warnings and Precautions]. ASCOR^® is not indicated for use in pediatric patients less than 5 months of age.

Geriatric Use

Glomerular filtration rate is known to decrease with age and as such may increase risk for oxalate nephropathy following ascorbic acid administration in elderly population [see Warnings and Precautions].

Renal Impairment

ASCOR^® should be used with caution in scorbutic patients with a history of or risk of developing renal oxalate stones or evidence of renal impairment or other issues (e.g., patients on dialysis, patients with diabetic nephropathy, and renal transplant recipients). These patients may be at increased risk of developing acute or chronic oxalate nephropathy following high dose ascorbic acid administration [see Warnings and Precautions].

OVERDOSAGE

Overdose with ascorbic acid may cause nausea, vomiting, diarrhea, facial flushing, rash, headache, fatigue or disturbed sleep. If overdose of ASCOR^® occurs, immediately discontinue administration and treat symptoms and signs of overdose, avoiding additional intake of ascorbic acid.