SUFLAVE

5 WARNINGS AND PRECAUTIONS Risk of fluid and electrolyte abnormalities : Encourage adequate hydration, assess concurrent medications and consider laboratory assessments prior to and after each 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 seizures, including medications that lower the seizure threshold. ( 5.3 , 7.1 ) Colonic mucosal ulcerations : Consider potential for ulcerations when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease. ( 5.5 ) 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 ) Suspected GI obstruction or perforation : Rule out the diagnosis before administration. ( 4 , 5.6 ) Patients at risk for aspiration : Observe during administration ( 5.7 ) Hypersensitivity reactions, including anaphylaxis : Inform patients to seek immediate medical care if symptoms occur ( 5.8 ) 5.1 Serious Fluid and Electrolyte Abnormalities Advise all patients to hydrate adequately before, during, and after the use of SUFLAVE. If a patient develops significant vomiting or signs of dehydration after taking SUFLAVE, consider performing post-colonoscopy lab tests (electrolytes, creatinine, and BUN). Bowel preparation products 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 SUFLAVE. Use SUFLAVE with caution in patients with conditions, or who are using medications [such as diuretics, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs)], that increase the risk for fluid and electrolyte disturbances or may increase the risk of seizure, arrhythmias, and renal impairment [see Drug Interactions ( 7.1 )] . 5.2 Cardiac Arrythmias There have been rare reports of serious arrhythmias 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 SUFLAVE for patients at increased risk of arrhythmias (e.g., patients with a history of prolonged QT interval, uncontrolled arrhythmias, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy). Consider pre-dose and post-colonoscopy ECGs in patients at increased risk of serious cardiac arrhythmias. 5.3 Seizures There have been 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 SUFLAVE 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 Risk of Renal Injury Use SUFLAVE with caution in patients with impaired renal function or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or non-steroidal 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 with SUFLAVE and consider performing baseline and postcolonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients [see Use in Specific Populations ( 8.6 )] . 5.5 Colonic Mucosal Ulcerations and Ischemic Colitis Osmotic laxative products 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 SUFLAVE may increase these risks [see Drug Interactions ( 7.3 )] . Consider the potential for mucosal ulcerations resulting from the bowel preparation when interpreting colonoscopy findings in patients with known or suspect 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 SUFLAVE [see Contraindications ( 4 )] . Use with caution in patients with severe active ulcerative colitis. 5.7 Aspiration Patients with impaired gag reflex or other swallowing abnormalities are at risk for regurgitation or aspiration of SUFLAVE. Observe these patients during administration of SUFLAVE. Do not combine SUFLAVE with starch-based thickeners [see Dosage and Administration ( 2.1 )] . Polyethylene glycol (PEG), a component of SUFLAVE, 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 Hypersensitivity Reactions SUFLAVE contains polyethylene glycol (PEG) and other ingredients that may cause serious hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, and pruritus [see Adverse Reactions ( 6.2 )] . Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur.

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 Risk of Renal Injury [see Warnings and Precautions ( 5.4 )] Colonic Mucosal Ulceration and Ischemic 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 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (≥2%) are: nausea, abdominal distension, vomiting, abdominal pain and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Braintree Laboratories, Inc. at 1-800-874-6756 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The safety of SUFLAVE was evaluated in two randomized, parallel group, multicenter, investigator-blinded clinical trials in 929 adult patients undergoing colonoscopy. The active comparators were polyethylene glycol 3350, sodium sulfate, sodium chloride, potassium chloride, ascorbic acid and sodium ascorbate for oral solution in Study 1 and sodium sulfate, potassium sulfate, and magnesium sulfate oral solution in Study 2 [see Clinical Studies ( 14 )] . Table 1 shows the most common adverse reactions reported in at least 2% of patients in either treatment group in Study 1. Table 1: Common Adverse Reactions a by Treatment Group in Adult Patients Undergoing Colonoscopy in Study 1 b a Reported in at least 2% of patients in either treatment group. b Study 1 was not designed to support comparative claims for SUFLAVE for the adverse reactions reported in this table. c Abdominal pain is composed of several similar terms. SUFLAVE (%) N=233 Polyethylene glycol 3350, sodium sulfate, sodium chloride, potassium chloride, ascorbic acid and sodium ascorbate for oral solution (%) N=243 Nausea 13 9 Abdominal distension 6 3 Vomiting 6 3 Abdominal pain c 3 4 Headache 3 2 Table 2 shows the most common adverse reactions reported in at least 2% of patients in either treatment group in Study 2. Table 2: Common Adverse Reactions a by Treatment Group in Adult Patients Undergoing Colonoscopy in Study 2 b a Reported in at least 2% of patients in any treatment group. b Study 2 was not designed to support comparative claims for SUFLAVE for the adverse reactions reported in this table. c Abdominal pain is composed of several similar items. SUFLAVE (%) N=227 Sodium sulfate, potassium sulfate, and magnesium sulfate oral solution (%) N=226 Nausea 7 6 Vomiting 4 7 Headache 2 2 Abdominal pain c 3 1 Abdominal distension 1 1 Laboratory Changes Electrolyte Abnormalities In patients with normal baseline values, the most common electrolyte abnormality following study drug, on the day of colonoscopy, was increased magnesium (Study 1: 11% in SUFLAVE-treated patients and 2% in patients treated with active comparator; Study 2: 12% in SUFLAVE-treated patients and 11% in patients treated with active comparator). These changes were transient and resolved without intervention. Renal Function Parameters In patients with normal baseline values, at 48 to 72 hours after bowel preparation, an increase in serum creatinine of > 0.3 mg/dL and/or a decrease in eGFR of > 25% were reported in 2% of SUFLAVE-treated patients and 0 patients treated with active comparator in Study 1 and 1% of SUFLAVE-treated patients and 3% of patients treated with active comparator in Study 2. These changes were transient and resolved. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of other polyethylene glycol-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 : arrhythmia, atrial fibrillation, peripheral edema, asystole, acute pulmonary edema [see Warnings and Precautions ( 5.2 )] . Gastrointestinal : upper gastrointestinal bleeding from a Mallory-Weiss tear; esophageal perforation, usually with gastroesophageal reflux disease Hypersensitivity reactions : rash, urticaria, pruritus, dermatitis, dyspnea, chest tightness and throat tightness, fever, angioedema, anaphylaxis and anaphylactic shock [see Warnings and Precautions ( 5.8 )] . Nervous system : tremor, seizure [see Warnings and Precautions ( 5.3 )]

<table ID="t1" width="100%"><caption>Table 1: Common Adverse Reactions ^a by Treatment Group in Adult Patients Undergoing Colonoscopy in Study 1 ^b</caption><col width="30.000%" align="left"/><col width="20.000%" align="left"/><col width="50.000%" align="left"/><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="First Footnote">^aReported in at least 2% of patients in either treatment group. </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="First Footnote">^bStudy 1 was not designed to support comparative claims for SUFLAVE for the adverse reactions reported in this table. </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="First Footnote">^cAbdominal pain is composed of several similar terms. </paragraph></td></tr></tfoot><tbody><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="middle"/><td align="center" valign="middle"><paragraph>SUFLAVE (%) N=233 </paragraph></td><td align="center" styleCode="Lrule Rrule" valign="middle"><paragraph>Polyethylene glycol 3350, sodium sulfate, sodium chloride, potassium chloride, ascorbic acid and sodium ascorbate for oral </paragraph><paragraph>solution (%) N=243 </paragraph></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Nausea</td><td align="center" styleCode="Rrule Toprule" valign="top">13</td><td align="center" styleCode="Botrule Rrule Toprule" valign="top">9</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Abdominal distension</td><td align="center" styleCode="Rrule Toprule" valign="top">6</td><td align="center" styleCode="Botrule Rrule Toprule" valign="top">3</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Vomiting</td><td align="center" styleCode="Botrule Rrule Toprule" valign="top">6</td><td align="center" styleCode="Botrule Rrule" valign="top">3</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Abdominal pain ^c</td><td align="center" styleCode="Botrule Rrule" valign="top">3</td><td align="center" styleCode="Botrule Rrule" valign="top">4</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Headache</td><td align="center" styleCode="Botrule Rrule" valign="top">3</td><td align="center" styleCode="Botrule Rrule" valign="top">2</td></tr></tbody></table>

<table ID="t2" width="100%"><caption>Table 2: Common Adverse Reactions ^a by Treatment Group in Adult Patients Undergoing Colonoscopy in Study 2 ^b</caption><col width="30.000%" align="left"/><col width="20.000%" align="left"/><col width="50.000%" align="left"/><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="First Footnote">^aReported in at least 2% of patients in any treatment group. </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="First Footnote">^bStudy 2 was not designed to support comparative claims for SUFLAVE for the adverse reactions reported in this table. </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="First Footnote">^cAbdominal pain is composed of several similar items. </paragraph></td></tr></tfoot><tbody><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="middle"/><td align="center" valign="middle"><paragraph>SUFLAVE (%) N=227 </paragraph></td><td align="center" styleCode="Lrule Rrule" valign="middle"><paragraph>Sodium sulfate, potassium sulfate, and magnesium sulfate oral solution (%) N=226 </paragraph></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Nausea</td><td align="center" styleCode="Rrule Toprule" valign="top">7</td><td align="center" styleCode="Botrule Rrule Toprule" valign="top">6</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Vomiting</td><td align="center" styleCode="Rrule Toprule" valign="top">4</td><td align="center" styleCode="Botrule Rrule Toprule" valign="top">7</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Headache</td><td align="center" styleCode="Botrule Rrule Toprule" valign="top">2</td><td align="center" styleCode="Botrule Rrule" valign="top">2</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Abdominal pain ^c</td><td align="center" styleCode="Botrule Rrule" valign="top">3</td><td align="center" styleCode="Botrule Rrule" valign="top">1</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"> Abdominal distension</td><td align="center" styleCode="Botrule Rrule" valign="top">1</td><td align="center" styleCode="Botrule Rrule" valign="top">1</td></tr></tbody></table>