PEG-3350, Electrolytes, and Ascorbate

5 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution. If a patient develops significant vomiting or signs of dehydration after taking Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution, 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution. Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution, 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution [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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution. Observe these patients during the administration of Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution. Use with caution in these patients. Do not combine Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution with starch-based thickeners [see Dosage and Administration (2.1)]. Polyethylene glycol (PEG), a component of Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution, 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution contains sodium ascorbate and ascorbic acid, Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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). Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution contains phenylalanine, a component of aspartame. Each Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution treatment contains 131 mg of phenylalanine (after hydrolysis of the aspartame molecule in vivo to aspartic acid and phenylalanine). Before prescribing Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution. 5.10 Hypersensitivity Reactions Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution. If a patient develops significant vomiting or signs of dehydration after taking Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution, 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution. Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 )].

6 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 Oceanside 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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 Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution 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.

<table ID="_RefID0EJVAE" width="100%"><caption>Table 1: Common Adverse Reactions<footnote ID="_Ref75256026">Reported in at least 2% of patients in either treatment group</footnote> in Patients Undergoing Colonoscopy in Study 1</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Polyethylene Glycol-3350, Electrolytes, and Ascorbate for Oral Solution </content></paragraph><paragraph><content styleCode="bold">Two-Day Split</content> <content styleCode="bold">Dosing Regimen</content></paragraph><paragraph><content styleCode="bold">(N=180)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">4 Liter PEG + </content> <content styleCode="bold">Electrolytes</content> <content styleCode="bold">Solution</content></paragraph><paragraph><content styleCode="bold">(N=179) </content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Malaise</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nausea</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>20%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Abdominal pain</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Vomiting</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Upper abdominal pain</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">Dyspepsia</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1%</paragraph></td></tr></tbody></table>