Ascorbic Acid

INDICATIONS AND USAGE 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.

DOSAGE AND ADMINISTRATION • 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

WARNINGS AND PRECAUTIONS • Risk of fluid and electrolyte abnormalities: Encourage adequate hydration, assess concurrent medications, and consider laboratory assessments prior to and after use. ( 5.1 , 7.1 ) • Cardiac arrhythmias: Consider pre-dose and post-colonoscopy ECGs in patients at increased risk. ( 5.2 ) • Seizures : Use caution in patients with a history of seizures and patients at increased risk of seizure, including medications that lower the seizure threshold. ( 5.3 , 7.1 ) • Patients with renal impairment or taking concomitant medications that affect renal function: Use caution, ensure adequate hydration and consider laboratory testing. ( 5.4 , 7.1 , 8.6 ) • Colonic mucosal ulcerations : Consider potential for ulcerations when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease. ( 5.5 ) • Suspected GI obstruction or perforation : Rule out the diagnosis before administration. ( 5.6 ) • Patients at risk for aspiration: Observe during administration. ( 5.7 ) • Glucose-6-phosphate dehydrogenase deficiency (G-6-PD) : Use with caution. ( 5.8 ) • Risks in patients with phenylketonuria : Contains phenylalanine ( 5.9 ) • Hypersensitivity reactions, including anaphylaxis : Inform patients to seek immediate medical care if symptoms occur. ( 5.10 ) 5.1 Serious Fluid and Electrolyte Abnormalities Advise patients to hydrate adequately before, during, and after the use of MoviPrep. If a patient develops significant vomiting or signs of dehydration after taking MoviPrep, consider performing post-colonoscopy lab tests (electrolytes, creatinine, and BUN). Bowel preparations can cause fluid and electrolyte disturbances, which can lead to serious adverse reactions including cardiac arrhythmias, seizures, and renal impairment [see Adverse Reactions ( 6.2 )] . Correct fluid and electrolyte abnormalities before treatment with MoviPrep. MoviPrep should be used with caution in patients using concomitant medications that increase the risk of electrolyte abnormalities [such as diuretics, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs)] or in patients with known or suspected hyponatremia. Consider performing pre-dose and post-colonoscopy laboratory tests (sodium, potassium, calcium, creatinine, and BUN) in these patients [see Drug Interactions ( 7.1 )]. 5.2 Cardiac Arrhythmias There have been rare reports of serious arrhythmias (including atrial fibrillation) associated with the use of ionic osmotic laxative products for bowel preparation. These occur predominantly in patients with underlying cardiac risk factors and electrolyte disturbances. Use caution when prescribing MoviPrep for patients at increased risk of arrhythmias (e.g., patients with a history of prolonged QT, uncontrolled arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, cardiomyopathy, or electrolyte imbalance). Consider pre-dose and post-colonoscopy ECGs in patients at increased risk of serious cardiac arrhythmias. 5.3 Seizures There have been rare reports of generalized tonic-clonic seizures and/or loss of consciousness associated with use of bowel preparation products in patients with no prior history of seizures. The seizure cases were associated with electrolyte abnormalities (e.g., hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia) and low serum osmolality. The neurologic abnormalities resolved with correction of fluid and electrolyte abnormalities. Use caution when prescribing MoviPrep for patients with a history of seizures and in patients at increased risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or benzodiazepines, or patients with known or suspected hyponatremia [see Drug Interactions ( 7.1 )]. 5.4 Use in Patients with Renal Impairment Use MoviPrep with caution in patients with renal impairment or patients taking concomitant medications that affect renal function (such as diuretics, ACE inhibitors, angiotensin receptor blockers, or nonsteroidal anti-inflammatory drugs) [see Drug Interactions ( 7.1 )]. These patients may be at risk for renal injury. Advise these patients of the importance of adequate hydration before, during, and after use of MoviPrep, and consider performing pre-dose and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients [see Use in Specific Populations ( 8.6 )]. 5.5 Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis Osmotic laxatives may produce colonic mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of stimulant laxatives and MoviPrep may increase the risk of mucosal ulceration or ischemic colitis and is not recommended. Consider the potential for mucosal ulcerations resulting from the bowel preparation when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease. 5.6 Use in Patients with Significant Gastrointestinal Disease If gastrointestinal obstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions before administering MoviPrep [see Contraindications ( 4 )] . Use with caution in patients with severe ulcerative colitis. 5.7 Aspiration Patients with impaired gag reflex or other swallowing abnormalities are at risk for regurgitation or aspiration of MoviPrep. Observe these patients during the administration of MoviPrep. Use with caution in these patients. Do not combine MoviPrep with starch-based thickeners [see Dosage and Administration ( 2.1 )] . Polyethylene glycol (PEG), a component of MoviPrep, when mixed with starch-thickened liquids reduces the viscosity of the starch-thickened liquid. When a PEG-based product used for another indication was mixed in starch-based pre-thickened liquids used in patients with dysphagia, thinning of the liquid occurred and cases of choking and potential aspiration were reported. 5.8 Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Since MoviPrep contains sodium ascorbate and ascorbic acid, MoviPrep should be used with caution in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, especially G6PD deficiency patients with an active infection, with a history of hemolysis, or taking concomitant medications known to precipitate hemolytic reactions. 5.9 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). MoviPrep contains phenylalanine, a component of aspartame. Each MoviPrep treatment contains 131 mg of phenylalanine (after hydrolysis of the aspartame molecule in vivo to aspartic acid and phenylalanine). Before prescribing MoviPrep to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including MoviPrep. 5.10 Hypersensitivity Reactions MoviPrep contains polyethylene glycol (PEG) and lemon flavoring (containing citral, lime oil, maltodextrin, acacia gum, vitamin E, and other natural flavoring agents) and may cause serious hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, and pruritus [see Contraindications (4) , Adverse Reactions (6.2) and Description (11) ] . Inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care should signs and symptoms occur. 5.1 Serious Fluid and Electrolyte Abnormalities Advise patients to hydrate adequately before, during, and after the use of MoviPrep. If a patient develops significant vomiting or signs of dehydration after taking MoviPrep, consider performing post-colonoscopy lab tests (electrolytes, creatinine, and BUN). Bowel preparations can cause fluid and electrolyte disturbances, which can lead to serious adverse reactions including cardiac arrhythmias, seizures, and renal impairment [see Adverse Reactions ( 6.2 )] . Correct fluid and electrolyte abn

CONTRAINDICATIONS MoviPrep is contraindicated in the following conditions: • Gastrointestinal (GI) obstruction [see Warnings and Precautions (5.6) ] • Bowel perforation [see Warnings and Precautions (5.6) ] • Gastric retention • Ileus • Toxic colitis or toxic megacolon • Hypersensitivity to any ingredient in MoviPrep [see Warnings and Precautions (5.10) and Description (11) ] • Gastrointestinal (GI) obstruction ( 4 , 5.6 ) • Bowel perforation ( 4 , 5.6 ) • Gastric retention ( 4 ) • Ileus ( 4 ) • Toxic colitis or toxic megacolon ( 4 ) • Hypersensitivity to any ingredient in MoviPrep ( 4 , 5.10 )

7. DRUG INTERACTIONS ​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 affect excretion and plasma concentrations of other drugs sensitive to urine pH (7.2). ​Warfarin:​ Continue standard monitoring (7.3) ​ See 17 for PATIENT COUNSELING INFORMATION ​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 affect excretion and plasma concentrations of other drugs sensitive to urine pH (7.2) . ​Warfarin: ​ Continue standard monitoring (7.3) ​ See 17 for PATIENT COUNSELING INFORMATION 7.1 Antibiotics 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 ASCOR, discontinue ASCOR administration. 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 ASCOR, discontinue ASCOR administration. 7.2 Amphetamine & Other Drugs Affected by Urine Acidification 7.2 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. 7.2 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. 7.3 Warfarin 7.3 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. 7.3 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. 7.4 Laboratory Test Interference 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) ] . 7.4 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 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 ASCOR, discontinue ASCOR administration. 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 ASCOR, discontinue ASCOR administration. 7.2 Amphetamine & Other Drugs Affected by Urine Acidification 7.2 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. 7.2 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. 7.3 Warfarin 7.3 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. 7.3 Warfarin

ADVERSE REACTIONS The following serious or otherwise important adverse reactions for bowel preparations are described elsewhere in the labeling: • Serious Fluid and Electrolyte Abnormalities [see Warnings and Precautions (5.1) ] • Cardiac Arrhythmias [see Warnings and Precautions (5.2) ] • Seizures [see Warnings and Precautions (5.3)] • Patients with Renal Impairment [see Warnings and Precautions (5.4)] • Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis [see Warnings and Precautions (5.5)] • Patients with Significant Gastrointestinal Disease [see Warnings and Precautions (5.6)] • Aspiration [see Warnings and Precautions (5.7)] • Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency [see Warnings and Precautions (5.8)] • Risks in Patients with Phenylketonuria [see Warnings and Precautions (5.9)] • Hypersensitivity Reactions [see Warnings and Precautions (5.10)] Most common adverse reactions (≥ 5%) are: • Two-Day (Split-Dose): malaise, nausea, abdominal pain, vomiting, and upper abdominal pain. ( 6.1 ) • One-Day (Evening-Only): abdominal distension, anal discomfort, thirst, nausea, abdominal pain, sleep disorder, rigors, hunger, malaise, vomiting, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of MoviPrep as a Two-Day Split-Dosing and One-Day Evening Only Dosing Regimen was evaluated in two randomized, active-controlled, multicenter, investigator-blinded clinical trials in adult patients scheduled to have an elective colonoscopy [see Clinical Studies (14) ] . The safety analysis for Study 1 included 359 adult patients ranging in age from 18 to 88 years (mean age 59), with 52% female and 48% male patients. The safety analysis for Study 2 included 340 adult patients ranging in age from 21 to 76 years (mean age 53), with 53% male and 47% female patients. Tables 1 and 2 display adverse reactions reported in at least 2% and 5% of patients in either treatment group in Study 1 and Study 2, respectively. Since diarrhea was considered as a part of the efficacy assessment, it was not defined as an adverse reaction in these trials. Table 1: Common Adverse Reactions Reported in at least 2% of patients in either treatment group in Patients Undergoing Colonoscopy in Study 1 MoviPrep Two-Day Split Dosing Regimen (N=180) 4 Liter PEG + Electrolytes Solution (N=179) Malaise 19% 18% Nausea 14% 20% Abdominal pain 13% 15% Vomiting 8% 13% Upper abdominal pain 6% 6% Dyspepsia 3% 1% Table 2: Common Adverse Reactions Reported in at least 5% of patients in either treatment group Patients were specifically asked about the occurrence of the following symptoms: shivering, anal irritations, abdominal bloating or fullness, sleep loss, nausea, vomiting, weakness, hunger sensation, abdominal cramps or pain, thirst sensation, and dizziness. in Patients Undergoing Colonoscopy in Study 2 MoviPrep One-Day Evening Only Dosing Regimen (N=169) 90 mL Oral Sodium Phosphate Solution (N=171) Abdominal distension 60% 41% Anal discomfort 51% 52% Thirst 47% 65% Nausea 47% 47% Abdominal pain 39% 32% Sleep disorder 35% 29% Rigors 34% 30% Hunger 30% 71% Malaise 27% 53% Vomiting 7% 8% Dizziness 7% 18% Headache 2% 5% Hypokalemia 0% 6% Hyperphosphatemia 0% 6% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of MoviPrep or other PEG-based products. 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. Cardiovascular: tachycardia, palpitations, hypertension, arrhythmia, atrial fibrillation, peripheral edema, asystole, acute pulmonary edema and syncope, and dehydration. Gastrointestinal: upper gastrointestinal bleeding from a Mallory-Weiss tear, esophageal perforation [usually with gastroesophageal reflux disease (GERD)]. Hypersensitivity reactions: anaphylaxis (some of which were severe, including shock), rash, urticaria, pruritus, lip, tongue and facial swelling, dyspnea, chest tightness and throat tightness, rhinorrhea, dermatitis, fever, and chills [ see Warnings and Precautions (5.10) ] . Nervous system: tremor, seizure. Renal: renal impairment and/or failure. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of MoviPrep as a Two-Day Split-Dosing and One-Day Evening Only Dosing Regimen was evaluated in two randomized, active-controlled, multicenter, investigator-blinded clinical trials in adult patients scheduled to have an elective colonoscopy [see Clinical Studies (14) ] . The safety analysis for Study 1 included 359 adult patients ranging in age from 18 to 88 years (mean age 59), with 52% female and 48% male patients. The safety analysis for Study 2 included 340 adult patients ranging in age from 21 to 76 years (mean age 53), with 53% male and 47% female patients. Tables 1 and 2 display adverse reactions reported in at least 2% and 5% of patients in either treatment group in Study 1 and Study 2, respectively. Since diarrhea was considered as a part of the efficacy assessment, it was not defined as an adverse reaction in these trials. Table 1: Common Adverse Reactions Reported in at least 2% of patients in either treatment group in Patients Undergoing Colonoscopy in Study 1 MoviPrep Two-Day Split Dosing Regimen (N=180) 4 Liter PEG + Electrolytes Solution (N=179) Malaise 19% 18% Nausea 14% 20% Abdominal pain 13% 15% Vomiting 8% 13% Upper abdominal pain 6% 6% Dyspepsia 3% 1% Table 2: Common Adverse Reactions Reported in at least 5% of patients in either treatment group Patients were specifically asked about the occurrence of the following symptoms: shivering, anal irritations, abdominal bloating or fullness, sleep loss, nausea, vomiting, weakness, hunger sensation, abdominal cramps or pain, thirst sensation, and dizziness. in Patients Undergoing Colonoscopy in Study 2 MoviPrep One-Day Evening Only Dosing Regimen (N=169) 90 mL Oral Sodium Phosphate Solution (N=171) Abdominal distension 60% 41% Anal discomfort 51% 52% Thirst 47% 65% Nausea 47% 47% Abdominal pain 39% 32% Sleep disorder 35% 29% Rigors 34% 30% Hunger 30% 71% Malaise 27% 53% Vomiting 7% 8% Dizziness 7% 18% Headache 2% 5% Hypokalemia 0% 6% Hyperphosphatemia 0% 6% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of MoviPrep or other PEG-based products. 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. Cardiovascular: tachycardia, palpitations, hypertension, arrhythmia, atrial fibrillation, peripheral edema, asystole, acute pulmonary edema and syncope, and dehydration. Gastrointestinal: upper gastrointestinal bleeding from a Mallory-Weiss tear, esophageal perforation [usually with gastroesophageal reflux disease (GERD)]. Hypersensitivity reactions: anaphylaxis (some of which were severe, including shock), rash, urticaria, pruritus, lip, tongue and facial swelling, dyspnea, chest tightness and throat tightness, rhinorrhea, dermatitis, fever, and chills [ see Warnings and Precautions (5.10) ] . Nervous system: tremor, seizure. Renal: renal impairment and/or failure.

12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The exact mechanism of action of ascorbic acid for the treatment of symptoms and signs of scurvy (a disorder caused by severe deficiency in vitamin C) is unknown; however, administration of ascorbic acid in patients with scurvy is thought to restore the body pool of ascorbic acid. 12.3 Pharmacokinetics In a single pharmacokinetic study, healthy male and female adults (n=8) were given a single intravenous dose of 1000 mg ascorbic acid (5 times the largest recommended single dose) infused over a 30 minute period. The mean peak exposure to ascorbic acid was 436.2 µM and occurred at the end of the 30 minute infusion. Distribution Ascorbic acid is distributed widely in the body, with large concentrations found in the liver, leukocytes, platelets, glandular tissues, and lens of the eye. Based on data from oral exposure, ascorbic acid is known to be distributed into breast milk and crosses the placental barrier. Elimination When the body is saturated with ascorbic acid, the plasma concentration will be about the same as that of the renal threshold; if further amounts are then administered, most of it is excreted in the urine. When body tissues are not saturated and plasma concentration is low, administration of ascorbic acid results in little or no renal excretion. The mean±SD (N=3) half-life observed in the single dose PK study as described above, was 7.4±1.4 h. Metabolism A major route of metabolism of ascorbic acid involves its conversion to urinary oxalate, presumably through intermediate formation of its oxidized product, dehydroascorbic acid. Excretion There is a renal threshold for ascorbic acid (v[A1] itamin C); the vitamin is excreted by the kidney in large amounts only when the plasma concentration exceeds this threshold, which is approximately 1.4 mg/100 mL. 12.1 Mechanism of Action The exact mechanism of action of ascorbic acid for the treatment of symptoms and signs of scurvy (a disorder caused by severe deficiency in vitamin C) is unknown; however, administration of ascorbic acid in patients with scurvy is thought to restore the body pool of ascorbic acid. 12.3 Pharmacokinetics In a single pharmacokinetic study, healthy male and female adults (n=8) were given a single intravenous dose of 1000 mg ascorbic acid (5 times the largest recommended single dose) infused over a 30 minute period. The mean peak exposure to ascorbic acid was 436.2 µM and occurred at the end of the 30 minute infusion. Distribution Ascorbic acid is distributed widely in the body, with large concentrations found in the liver, leukocytes, platelets, glandular tissues, and lens of the eye. Based on data from oral exposure, ascorbic acid is known to be distributed into breast milk and crosses the placental barrier. Elimination When the body is saturated with ascorbic acid, the plasma concentration will be about the same as that of the renal threshold; if further amounts are then administered, most of it is excreted in the urine. When body tissues are not saturated and plasma concentration is low, administration of ascorbic acid results in little or no renal excretion. The mean±SD (N=3) half-life observed in the single dose PK study as described above, was 7.4±1.4 h. Metabolism A major route of metabolism of ascorbic acid involves its conversion to urinary oxalate, presumably through intermediate formation of its oxidized product, dehydroascorbic acid. Excretion There is a renal threshold for ascorbic acid (Vitamin C); the vitamin is excreted by the kidney in large amounts only when the plasma concentration exceeds this threshold, which is approximately 1.4 mg/100 mL. 12.1 Mechanism of Action The exact mechanism of action of ascorbic acid for the treatment of symptoms and signs of scurvy (a disorder caused by severe deficiency in vitamin C) is unknown; however, administration of ascorbic acid in patients with scurvy is thought to restore the body pool of ascorbic acid. 12.3 Pharmacokinetics In a single pharmacokinetic study, healthy male and female adults (n=8) were given a single intravenous dose of 1000 mg ascorbic acid (5 times the largest recommended single dose) infused over a 30 minute period. The mean peak exposure to ascorbic acid was 436.2 µM and occurred at the end of the 30 minute infusion. Distribution Ascorbic acid is distributed widely in the body, with large concentrations found in the liver, leukocytes, platelets, glandular tissues, and lens of the eye. Based on data from oral exposure, ascorbic acid is known to be distributed into breast milk and crosses the placental barrier. Elimination When the body is saturated with ascorbic acid, the plasma concentration will be about the same as that of the renal threshold; if further amounts are then administered, most of it is excreted in the urine. When body tissues are not saturated and plasma concentration is low, administration of ascorbic acid results in little or no renal excretion. The mean±SD (N=3) half-life observed in the single dose PK study as described above, was 7.4±1.4 h. Metabolism A major route of metabolism of ascorbic acid involves its conversion to urinary oxalate, presumably through intermediate formation of its oxidized product, dehydroascorbic acid. Excretion There is a renal threshold for ascorbic acid (Vitamin C); the vitamin is excreted by the kidney in large amounts only when the plasma concentration exceeds this threshold, which is approximately 1.4 mg/100 mL.