Plenvu

1 INDICATIONS AND USAGE PLENVU ® is indicated for cleansing of the colon in preparation for colonoscopy in adults. PLENVU is an osmotic laxative indicated for cleansing of the colon in preparation for colonoscopy in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION Preparation and Administration: • Two doses of PLENVU are required for a complete preparation for colonoscopy, using a “Two-Day” or “One-Day” dosage regimen. ( 2.1 ) • Reconstitute PLENVU in water prior to ingestion. ( 2.1 ) • Consume additional clear liquids after each dose of PLENVU in both dosing regimens. ( 2.1 , 5.1 ) • Administer oral medications at least 1 hour before starting each dose of PLENVU. ( 2.1 , 7.2 ) Recommended Dosage Regimens: • Two-Day Split Dosage : Dose 1 the evening before the colonoscopy (approximately 4 pm to 8 pm) and Dose 2 the next morning (approximately12 hours after the start of Dose 1). ( 2.1 , 2.2 ) • One-Day Morning Dosage : Dose 1 the morning of the colonoscopy (approximately 3 am to 7 am) and Dose 2 a minimum of 2 hours after the start of Dose 1. ( 2.1 , 2.3 ) • For complete information on dosing, preparation and administration, see full prescribing information. ( 2.1 , 2.2 , 2.3 ) 2.1 Important Preparation and Administration Instructions • Correct fluid and electrolyte abnormalities before treatment with PLENVU [see Warnings and Precautions ( 5.1 )] . • Two doses of PLENVU are required for a complete preparation for colonoscopy. The time interval between the two doses depends on the regimen prescribed and the planned timing of the colonoscopy procedure [see Dosage and Administration ( 2.2 , 2.3 )] . • The recommended “Two-Day Split Dosage” method consists of two separate doses: the first dose is taken the evening before the colonoscopy and the second dose is taken the next day, the morning of the day of the colonoscopy [see Dosage and Administration ( 2.2 )]. • The recommended “One-Day Morning Dosage” method consists of two separate doses: both doses are taken in the morning of the day of the colonoscopy, with a minimum of 2 hours between the start of the first dose and the start of the second dose [see Dosage and Administration ( 2.3 )]. • Reconstitute each pouch of PLENVU in the mixing container with water prior to ingestion. It may take 2 to 3 minutes for complete dissolution. Do not reconstitute with other liquids and/or add starch-based thickeners to the mixing container [see Warnings and Precautions ( 5.7 )]. • Consume additional clear liquids (including water) in both dosing regimens [see Dosage and Administration ( 2.2 , 2.3 ), Warnings and Precautions ( 5.1 )] . • Consume only clear liquids (no solid food) from the start of PLENVU treatment until after the colonoscopy. • Do not eat or drink alcohol, milk, anything colored red or purple or any other foods containing pulp material. • Do not take other laxatives while taking PLENVU. • Administer oral medications at least 1 hour before starting each dose of PLENVU [see Drug Interactions ( 7.2 )]. • Ensure completion of Dose 2, including all additional liquids, at least 2 hours before the colonoscopy. 2.2 Recommended Two-Day Split Dosage Regimen The recommended Two-Day Split Dosage regimen commences in the evening of the day before the colonoscopy. Instruct adult patients that on the day before the clinical procedure, they can consume a light breakfast followed by a light lunch, which must be completed at least 3 hours prior to the start of the first PLENVU dose. Instruct patients to take two separate doses in conjunction with clear liquids as follows: Dose 1 – In the evening before the colonoscopy, between approximately 4 pm and 8 pm: 1. Empty the contents of Dose 1 into the mixing container that comes with PLENVU. 2. Add water to the fill line on the mixing container (at least 16 fluid ounces). Do not add other ingredients to the PLENVU solution. 3. Thoroughly mix with a spoon or shake with lid on securely until completely dissolved (which may take 2 to 3 minutes). 4. Drink over the next 30 minutes. Be sure to drink all of the solution. 5. Refill the mixing container to the fill line (at least 16 fluid ounces) with clear liquids and drink over the next 30 minutes. 6. Consume additional clear liquids during …

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 , 5.2 , 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 testing. ( 5.4 , 7.1 , 8.6 ) • Mucosal ulcerations : Consider potential for mucosal ulcerations when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease. ( 5.5 ) • Suspected GI obstruction or perforation : Rule out diagnosis before administration. ( 4 , 5.6 ) • Patients at risk for aspiration : Observe during administration. ( 5.7 ) • Glucose-6-phosphate dehydrogenase deficiency (G6PD): 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 PLENVU. If a patient develops significant vomiting or signs of dehydration after taking PLENVU, consider performing post-colonoscopy laboratory 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. Correct fluid and electrolyte abnormalities before treatment with PLENVU. PLENVU 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)] [see Drug Interactions ( 7.1 )] . Consider performing pre-dose and post-colonoscopy laboratory tests (sodium, potassium, calcium, creatinine, and BUN) in patients receiving these concomitant medications. 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 PLENVU 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 PLENVU 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 PLENVU with caution in patients with renal impairment or patients taking concomitant medications that affect renal function (such as diuretics, ACE inhibito…

4 CONTRAINDICATIONS PLENVU 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 megacolon • Hypersensitivity to any ingredient in PLENVU [see Warnings and Precautions ( 5.10 )] • Gastrointestinal (GI) obstruction ( 4 , 5.6 ) • Bowel perforation ( 4 , 5.6 ) • Gastric retention ( 4 ) • Ileus ( 4 ) • Toxic megacolon ( 4 ) • Hypersensitivity to any ingredient in PLENVU ( 4 , 5.10 )

7 DRUG INTERACTIONS Drugs that increase risks due to fluid and electrolyte changes. ( 7.1 ) 7.1 Drugs That May Increase Risks Due to Fluid and Electrolyte Abnormalities Use caution when prescribing PLENVU for patients with conditions and/or who are using medications that increase the risk of fluid and electrolyte disturbances or may increase the risk of renal impairment, seizures, arrhythmias, or QT prolongation in the setting of fluid and electrolyte abnormalities [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , 5.4 )]. Consider additional patient evaluations as appropriate. 7.2 Potential for Reduced Drug Absorption PLENVU can reduce the absorption of other coadministered oral drugs . Administer oral medications at least 1 hour before starting each dose of PLENVU [see Dosage and Administration ( 2.1 )]. 7.3 Stimulant Laxatives Concurrent use of stimulant laxatives and PLENVU may increase the risk of mucosal ulceration or ischemic colitis. Avoid use of stimulant laxatives (e.g., bisacodyl, sodium picosulfate) while taking PLENVU [see Warnings and Precautions ( 5.5 )] .

8.1 Pregnancy Risk Summary There are no available data with PLENVU in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Animal reproduction studies have not been conducted with PLENVU. 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% to 4% and 15% to 20%, respectively.

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 (>2%) are nausea, vomiting, dehydration and abdominal pain/discomfort. ( 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 Trials 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 practice. The safety of PLENVU Two-Day Split Dosage and One-Day Morning Dosage regimens was evaluated in two randomized, parallel group, multicenter, investigator-blinded clinical trials (Two-Day Split Dosage in the NOCT and MORA trials and One-Day Morning Dosage in the MORA trial) in 1351 adult patients undergoing colonoscopy. The mean age of the study population was 56 years (range 18 to 86 years), 92% of patients were Caucasian and 51% were female. In the NOCT trial, 61% of patients had mild renal impairment. In the MORA trial, 67% had mild renal impairment and 5% had moderate renal impairment. Patients with severe renal impairment were not enrolled in the clinical trials of PLENVU [see Clinical Studies ( 14 )]. The most common adverse reactions (>2%) in the PLENVU treatment groups in both trials were: nausea, vomiting, dehydration and abdominal pain/discomfort. Table 1 and Table 2 display adverse reactions reported in at least 1% of patients in one or more treatment group(s) in the NOCT and MORA trials, 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* in Patients Undergoing Colonoscopy in the NOCT Trial by Treatment Group Preferred Term PLENVU Two-Day Split Dosage Regimen (N = 275) % Trisulfate Trisulfate: Two 6-ounce bottles of oral solution each containing sodium sulfate 17.5 grams, potassium sulfate 3.13 grams, magnesium sulfate 1.6 grams Two-Day Split Dosage Regimen (N = 271) % Nausea 7 2 Vomiting 6 3 Dehydration Includes signs and symptoms of dehydration, including dizziness, dry mouth, orthostatic hypotension, pre-syncope, syncope, and thirst 4 2 Abdominal Pain/Discomfort Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and abdominal tenderness 2 2 Decline in Glomerular Filtration Rate (GFR) Decreased or abnormal GFR 2 2 Electrolyte Abnormalities Includes increased anion gap, decreased blood bicarbonate, hypomagnesemia, hyperosmolarity, hypokalemia, hyperkalemia, hypercalcemia, hypernatremia, hyperosmolar state, hyperuricemia, hypocalcemia, and hypophosphatemia 2 1 Fatigue 2 1 Headache 2 1 Abdominal Distension 1 1 Gastritis 1 1 Hiatus Hernia 1 0 Nasopharyngitis 1 1 * Reported in at least 1% of patients in either treatment group N = Total number of patients in the treatment group Table 2: Common Adverse Reactions* in Patients Undergoing Colonoscopy in the MORA Trial by Treatment Group Preferred Term PLENVU One-Day Morning Dosage Regimen (N…