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 (approximately 12 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 the evening. 7. If severe bloating, abdominal distention, or abdominal pain occurs following the first dose, delay the second dose until the symptoms resolve. Dose 2 – The next morning, on the day of the colonoscopy, approximately 12 hours after the start of Dose 1 (between approximately 4 am and 8 am): 1. Empty the contents of Dose 2 Pouch A and Dose 2 Pouch B 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). Drink over the next 30 minutes. Be sure to drink all of the solution. 4. Refill the mixing container to the fill line (at least 16 fluid ounces) with clear liquids and drink over the next 30 minutes. 5. Consume additional water or clear liquids up to 2 hours before the colonoscopy or as prescribed by your doctor. Then stop drinking liquids until after the colonoscopy. Stop drinking PLENVU temporarily or drink each portion at longer intervals if severe bloating, abdominal discomfort or distention occurs, until these symptoms resolve. 2.3 Recommended One-Day Morning Dosage Regimen The recommended One-Day Morning Dosage regimen commences in the morning of the day of the colonoscopy. Instruct adult patients that on the day before the clinical procedure, they can consume a light breakfast followed by a light lunch, and clear broth soup and/or plain yogurt for dinner, which should be completed by approximately 8 pm. Instruct patients to take two separate doses in conjunction with clear liquids as follows: Dose 1 – On the day of the colonoscopy, between approximately 3 am and 7 am: 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. If severe bloating, abdominal distention, or abdominal pain occurs following the first dose, delay the second dose until the symptoms resolve. Dose 2 – On the day of the colonoscopy, a minimum of 2 hours after the start of Dose 1: 1. Empty the contents of Dose 2 Pouch A and Dose 2 Pouch B 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). Drink over the next 30 minutes. Be sure to drink all of the solution. 4. Refill the mixing container to the fill line (at least 16 fluid ounces) with clear liquids and drink over the next 30 minutes. 5. Consume additional water or clear liquids up to 2 hours before the colonoscopy or as prescribed by your doctor. Then stop drinking liquids until after the colonoscopy. Stop drinking PLENVU temporarily or drink each portion at longer intervals if severe bloating, abdominal discomfort or distention occurs, until these symptoms resolve. Storage: After reconstitution, keep PLENVU solution at room temperature, between 68°F to 77°F (20°C to 25°C) [see USP Controlled Room Temperature]. The solution may also be stored in a refrigerator. Use within 24 hours after it is mixed in water.

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 )

Not available.

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 = 271) % PLENVU Two-Day Split Dosage Regimen (N = 265) % 2 Liter PEG + Electrolytes Two-Day Split Dosage Regimen 2 Liter PEG Plus Electrolytes: Two doses each containing PEG 3350 100 grams, sodium sulfate 7.5 grams, sodium chloride 2.691 grams, potassium chloride 1.015 grams, sodium ascorbate 5.9 grams, and ascorbic acid 4.7 grams (N = 269) % Vomiting 7 4 1 Nausea 6 6 3 Dehydration Includes signs and symptoms of dehydration, including dizziness, dry mouth, orthostatic hypotension, pre-syncope, syncope, and thirst 4 3 2 Abdominal Pain/Discomfort Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, and abdominal tenderness 3 2 3 Hypertension 2 1 0 Headache 1 2 2 Electrolyte Abnormalities Includes increased anion gap, decreased blood bicarbonate, hypomagnesemia, increased blood osmolarity, hypokalemia, hyperkalemia, hypercalcemia, hypernatremia, hyperosmolar state, hyperuricemia, hypocalcemia, and hypophosphatemia 1 1 0 * Reported in at least 1% of patients in either treatment group N = Total number of patients in the treatment group Electrolyte Changes Increases in serum sodium, chloride, calcium, magnesium, phosphate, and urate were noted in more patients treated with PLENVU compared with control in one or both trials. The majority of these changes were transient and not clinically significant. Associated decreases in bicarbonate and increases in serum osmolality were also noted. Renal Function Decreases in creatinine clearance and increases in blood urea nitrogen (BUN) were also noted in more patients treated with PLENVU compared to control in both trials. Changes of a magnitude indicative of possible acute renal injury, or worsening of baseline chronic renal impairment, were noted infrequently and occurred at a similar incidence in both PLENVU and comparator arms. Adverse reactions in patients with mild renal impairment were similar to those in patients with normal renal function . Less Common Adverse Reactions Less common adverse reactions (less than 1%) in the NOCT and MORA trials include: anorectal discomfort, hypersensitivity reaction (including rash), migraine, somnolence, asthenia, chills, pains, aches, palpitation, sinus tachycardia, hot flush, and transient increase in liver enzymes. An additional 235 patients were exposed to the One-Day Morning Dosage Regimen of PLENVU in a third clinical trial, utilizing a comparator not approved in the United States. The adverse reaction profile for patients receiving PLENVU in that trial was similar to what is described above. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of another oral formulation of polyethylene glycol 3350, sodium ascorbate, sodium sulfate, ascorbic acid, sodium chloride and potassium chloride or other polyethylene glycol (PEG)-based bowel preparations. 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. Hypersensitivity: urticaria/rash, pruritus, dermatitis, rhinorrhea dyspnea, chest and throat tightness, fever, angioedema, anaphylaxis and anaphylactic shock [see Contraindications ( 4 )] Cardiovascular: arrhythmia, atrial fibrillation, peripheral edema, asystole, and acute pulmonary edema after aspiration Gastrointestinal: upper gastrointestinal bleeding from a Mallory-Weiss tear, esophageal perforation [usually with gastroesophageal reflux disease (GERD)] Nervous system: tremor, seizure