2.1 Important Preparation and Administration Instructions

• Correct fluid and electrolyte abnormalities before administration of Prepopik [see Warnings and Precautions (5.1)].
• Two doses (one packet per dose) of Prepopik are required for a complete preparation for colonoscopy either as a Split-Dose (preferred) or Day-Before dosing regimen.
• The preferred method is the "Split-Dose" method and consists of two separate doses: the first dose during the evening before the colonoscopy and the second dose the next day, the morning of the day of the colonoscopy [see Dosage and Administration (2.2)].
• The alternative method is the "Day Before" method and consists of two separate doses: the first dose during the afternoon or early evening before the colonoscopy and the second dose 6 hours later during the evening before the colonoscopy [see Dosage and Administration (2.3)].
• Each packet of Prepopik must be dissolved in 5 ounces of cold water prior to ingestion and administered according to the dosing regimen. Direct ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration and electrolyte disturbances [see Warnings and Precautions (5.8)].
• Additional fluids must be consumed after every dose of Prepopik in both dosing regimens [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].
• Consume only clear fluids (no solid food) from the start of Prepopik treatment until after the colonoscopy.
• Do not eat solid food or dairy and do not drink anything colored red or purple.
• Do not drink alcohol.
• Do not take other laxatives while taking Prepopik
• Do not take oral medications within one hour before or after starting Prepopik.
• If taking tetracycline or fluoroquinolone antibiotics, iron, digoxin, chlorpromazine, or penicillamine, take these medications at least 2 hours before and not less than 6 hours after administration of Prepopik [see Drug Interactions (7.2)].
• Stop consumption of all fluids at least 2 hours before the colonoscopy.

2.2 Reconstitution of Prepopik Powder

1. Reconstitute the Prepopik powder immediately before each administration. Do not prepare the solution in advance.
2. Fill the supplied dosing cup with cold water up to the lower (5-ounce) line on the cup and pour in the contents of one packet of Prepopik powder.
3. Stir for 2 to 3 minutes. The reconstituted Prepopik solution may become slightly warm as the powder dissolves.

2.3 Split-Dose Dosing Regimen (Preferred Method)

The Split-Dose regimen is the preferred dosing method. The recommended dosage in adults and pediatric patients 9 years of age and older is shown below. Instruct patients to take two separate doses (one packet per dose) in conjunction with fluids.

2.4 Day-Before Dosing Regimen (Alternative Method)

The Day-Before regimen is the alternative dosing method for patients for whom the Split-Dosing is inappropriate. The recommended dosage in adults and pediatric patients 9 years of age and older is shown below. Instruct patients to take two separate doses (one packet per dose) in conjunction with fluids

5.1 Serious Fluid and Electrolyte Abnormalities

Advise patients to hydrate adequately before, during, and after the use of Prepopik. Use caution in patients with congestive heart failure when replacing fluids. If a patient develops significant vomiting or signs of dehydration including signs of orthostatic hypotension after taking Prepopik, consider performing post-colonoscopy lab tests (electrolytes, creatinine, and BUN) and treat accordingly. Approximately 20% of adult patients in both arms (Prepopik, 2L of PEG + E plus two × 5-mg bisacodyl tablets) of clinical trials of Prepopik had orthostatic changes (changes in blood pressure and/or heart rate) on the day of colonoscopy. In adult clinical trials orthostatic changes were documented up to seven days post colonoscopy. In a single study of patients 9 to 16 years of age, approximately 20% of patients in Prepopik arms had orthostatic changes (changes in blood pressure and/or heart rate) compared with approximately 7% of those who received the comparator (PEG) [see Clinical Studies (14)]. These changes occurred up to five days post colonoscopy.

Fluid and electrolyte disturbances can lead to serious adverse reactions including cardiac arrhythmias or seizures and renal impairment. Correct fluid and electrolyte abnormalities before treatment with Prepopik . In addition, use caution when prescribing Prepopik for patients who have conditions or who are using medications that increase the risk for fluid and electrolyte disturbances or that may increase the risk of adverse events of seizure, arrhythmia, and renal impairment . Fluid and electrolyte disturbances can lead to serious adverse reactions including cardiac arrhythmias or seizures and renal impairment. Correct fluid and electrolyte abnormalities before treatment with Prepopik [see Dosage and Administration (2.1)]. In addition, use caution when prescribing Prepopik for patients who have conditions or who are using medications that increase the risk for fluid and electrolyte disturbances or that may increase the risk of adverse events of seizure, arrhythmia, and renal impairment [see Drug Interactions (7.1)].

5.2 Cardiac Arrhythmias

There have been rare reports of serious arrhythmias associated with the use of ionic osmotic laxative products for bowel preparation. Use caution when prescribing Prepopik 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, 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 with the 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 Prepopik for patients with a history of seizures and in patients at 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 Adverse Reactions (6.2)].

5.4 Use in Patients with Renal Impairment

Prepopik is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min), accumulation of magnesium in plasma may occur [see Contraindications (4)]. As with other magnesium containing bowel preparations, use caution when prescribing Prepopik for patients with mild to moderate renal impairment 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 increased risk for renal injury. Advise these patients of the importance of adequate hydration before, during and after the use of Prepopik. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients.

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 additional stimulant laxatives with Prepopik may increase this risk. The potential for mucosal ulcerations should be considered when interpreting colonoscopy findings in patients with known or suspected inflammatory bowel disease [see Adverse Reactions (6.2)].

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 Prepopik [see Contraindications (4)]. Use with caution in patients with severe active ulcerative colitis.

5.7 Aspiration

Patients with impaired gag reflex are at risk for regurgitation or aspiration during the administration of Prepopik. Observe these patients during the administration of Prepopik. Use with caution in these patients.

5.8 Risk of Vomiting and Other Gastrointestinal Complications with Ingestion of Undissolved Powder

Each packet must be dissolved in 5 ounces of cold water and administered at separate times according to the dosing regimen [see Dosage and Administration (2.3, 2.4)]. Ingestion of additional water is important to patient tolerance. Direct ingestion of the undissolved powder may increase the risk of nausea, vomiting, dehydration, and electrolyte disturbances.

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 clinical trials of another drug and may not reflect the rates observed in practice.

In randomized, multicenter, controlled clinical trials, nausea, headache, and vomiting were the most common adverse reactions (>1%) following Prepopik administration. The patients were not blinded to the study drug. Since abdominal bloating, distension, pain/cramping, and watery diarrhea are known to occur in response to colon cleansing preparations, these effects were documented as adverse events in the clinical trials only if they required medical intervention (such as a change in study drug or led to study discontinuation, therapeutic or diagnostic procedures, met the criteria for a serious adverse event), or showed clinically significant worsening during the study that was not in the frame of the usual clinical course, as determined by the investigator.

Prepopik was compared for colon cleansing effectiveness with a preparation containing two liters (2L) of polyethylene glycol plus electrolytes solution (PEG + E) and two 5-mg bisacodyl tablets, all administered the day before the procedure. Table 1 displays the most common adverse reactions in Study 1 and Study 2 for the Prepopik Split-Dose and Day-Before dosing regimens, respectively, each as compared to the comparator preparation.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of other oral formulations of sodium picosulfate, magnesium oxide and anhydrous citric acid similar to Prepopik. 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: rash, urticaria, purpura, and anaphylaxis [see Contraindications (4)]

Gastrointestinal: abdominal pain, diarrhea, fecal incontinence, aphthoid ileal ulcers, ischemic colitis [see Warnings and Precautions (5.5)]

Neurologic: generalized tonic-clonic seizures with and without hyponatremia in epileptic patients [see Warnings and Precautions (5.3)].

7.1 Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities

Use caution when prescribing Prepopik for patients with conditions and/or who are taking other drugs that increase the risk for 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)].

7.2 Potential for Reduced Drug Absorption

Prepopik can reduce the absorption of other co-administered drugs [see Dosage and Administration (2.1)]:

• Administer oral medications at least one hour before of the start of administration of Prepopik.
• Administer tetracycline and fluoroquinolone antibiotics [see Drug Interactions (7.3)], iron, digoxin, chlorpromazine, and penicillamine at least 2 hours before and not less than 6 hours after administration of Prepopik.

7.3 Antibiotics

Prior or concomitant use of antibiotics with Prepopik may reduce efficacy of Prepopik as conversion of sodium picosulfate to its active metabolite BHPM is mediated by colonic bacteria.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of Prepopik have been established for cleansing of the colon as a preparation for colonoscopy in pediatric patients 9 years of age and older. Use of Prepopik in this age group is supported by evidence from adequate and well-controlled trials of Prepopik in adults and a single, dose-ranging, controlled trial in 78 pediatric patients 9 to 16 years of age [see Clinical Studies (14)]. The safety profile of Prepopik in this pediatric population was similar to that seen in adults [see Adverse Reactions (6.1)]. Monitor for possible hypoglycemia in pediatric patients, as Prepopik has no caloric substrate.

The safety and effectiveness of Prepopik in pediatric patients less than 9 years of age have not been established.

8.5 Geriatric Use

Of the 1201 patients in clinical trials who received Prepopik, 215 (18%) patients were 65 years of age or older. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients. However, elderly patients are more likely to have decreased hepatic, renal or cardiac function and may be more susceptible to adverse reactions resulting from fluid and electrolyte abnormalities [see Warnings and Precautions (5.1)].

8.6 Renal Impairment

Prepopik is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 mL/min), as accumulation of magnesium in plasma may occur [see Contraindications (4)]. Patients with mild to moderate renal impairment or patients taking concomitant medications that may affect renal function may be at increased risk for renal injury [see Warnings and Precautions (5.4). Advise these patients of the importance of adequate hydration before, during and after the use of Prepopik [see Dosage and Administration (2.1)]. Consider performing baseline and post-colonoscopy laboratory tests (electrolytes, creatinine, and BUN) in these patients.

12.1 Mechanism of Action

Sodium picosulfate is hydrolyzed by colonic bacteria to form an active metabolite: bis-(p-hydroxy-phenyl)-pyridyl-2-methane, BHPM, which acts directly on the colonic mucosa to stimulate colonic peristalsis.

Magnesium oxide and citric acid react to create magnesium citrate in solution, which is an osmotic agent that causes water to be retained within the gastrointestinal tract.

12.2 Pharmacodynamics

The stimulant laxative activity of sodium picosulfate together with the osmotic laxative activity of magnesium citrate produces a purgative effect which, when ingested with additional fluids, produces watery diarrhea.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic potential have not been performed with Prepopik. Sodium picosulfate was not mutagenic in the Ames test, the mouse lymphoma assay and the mouse bone marrow micronucleus test.

In an oral fertility study in rats, Prepopik did not cause any significant adverse effect on male or female fertility parameters up to a maximum dose of 2000 mg/kg twice daily (about 1.2 times the recommended human dose based on the body surface area).

Adults

The colon cleansing efficacy of Prepopik was evaluated for non-inferiority against a comparator in two randomized, investigator-blinded, active-controlled, multicenter US trials in adult patients scheduled to have an elective colonoscopy. In all, 1195 adult patients were included in the primary efficacy analysis: 601 from Study 1, and 594 from Study 2. Patients ranged in age from 18 to 80 years (mean age 56 years); 61% were female and 39% male. Self-identified race was distributed as follows: 90% White, 10% Black, and less than 1% other. Of these, 3% self-identified their ethnicity as Hispanic or Latino.

Patients randomized to Prepopik in the two studies were treated with one of two dosing regimens:

• In Study 1, Prepopik was given by "Split-Dose" (evening before and day of) dosing, where the first packet was taken the evening before the colonoscopy (between 5:00 and 9:00 PM), followed by five (5) 8-ounce glasses of clear liquid, and the second packet was taken the morning of the colonoscopy (at least 5 hours prior to but no more than 9 hours prior to colonoscopy), followed by three (3) 8-ounce glasses of clear liquid.
• In Study 2, Prepopik was given by "Day-Before" (afternoon/evening before only) dosing, where both packets were taken separately on the day before the colonoscopy, with the first packet taken in the afternoon (between 4:00 and 6:00 PM), followed by five (5) 8-ounce glasses of clear liquid, and the second packet taken in the late evening (approximately 6 hours later, between 10:00 PM and 12:00 AM), followed by three (3) 8-ounce glasses of clear liquid.

The comparator was a preparation containing two liters of polyethylene glycol plus electrolytes solution (PEG + E) and two 5-mg bisacodyl tablets, administered the day before the procedure. All patients in both the Prepopik and comparator groups were limited to a clear liquid diet on the day before the procedure (24 hours before).

The primary efficacy endpoint was the proportion of patients with successful colon cleansing, as assessed by blinded colonoscopists using the Aronchick Scale. The Aronchick scale is a tool used to assess overall colon cleansing. Successful colon cleansing was defined as bowel preparations with >90% of the mucosa seen and mostly liquid stool that were graded excellent (minimal suctioning needed for adequate visualization) or good (significant suctioning needed for adequate visualization) by the colonoscopist.

In both studies, Prepopik was non-inferior to the comparator. In addition, Prepopik provided by Split-Dose dosing met the pre-specified criteria for superiority to the comparator for colon cleansing in Study 1. The comparator in that study was administered entirely on the day prior to colonoscopy. See Tables 3 and 4 below.

Pediatric Patients 9 Years of Age and Older

Prepopik was evaluated for colon cleansing in a randomized, assessor-blind, multicenter, dose-ranging, active-controlled study in 78 pediatric patients 9 years to 16 years of age. The majority of patients were female (68%), white (91%), and of non-Hispanic or non-Latino ethnicity (95%). The mean age was 12 years of age. All 78 patients were included in the primary efficacy analysis.

Patients aged 9 years to 12 years were randomized into 3 arms (1:1:1):

• Prepopik one-half packet administered as two doses
• Prepopik one-packet administered as two doses
• comparator (oral PEG-based solution per local standard of care).

Patients aged 13 years to 16 years were randomized into 2 arms (1:1):

• Prepopik one-packet administered as two doses
• comparator (oral PEG-based solution per local standard of care)

Patients randomized to Prepopik had two options for dosing, as determined by the investigator. The "Split Dose" regimen was the preferred method and the "Day Before" regimen was the alternative method if the "Split Dose" was not appropriate.

"Split-Dose" Regimen: (evening before and day of) dosing, where the first dose was taken the evening before the colonoscopy (between 5:00 and 9:00 PM), followed by five (5) 8-ounce glasses of clear liquid, and the second dose was taken the morning of the colonoscopy (at least 5 hours prior to but no more than 9 hours prior to colonoscopy), followed by three (3) 8-ounce glasses of clear liquid.

"Day-Before" Regimen: (afternoon/evening before only) dosing, where both doses were taken separately on the day before the colonoscopy, with the first dose taken in the afternoon (between 4:00 and 6:00 PM), followed by five (5) 8-ounce glasses of clear liquid, and the second dose taken in the late evening (approximately 6 hours later, between 10:00 PM and 12:00 AM), followed by three (3) 8-ounce glasses of clear liquid.

All patients randomized to Prepopik were limited to a clear liquid diet on the day before the procedure. Those who received the comparator were given dietary instructions per the trial site's standard of care.

The primary efficacy endpoint was the proportion of patients with successful colon cleansing as defined as a rating of either "Excellent" (> 90% of mucosa seen, mostly liquid stool, minimal suctioning needed for adequate visualization) or "Good" (> 90% of mucosa seen, mostly liquid stool, significant suctioning needed for adequate visualization) using the Aronchick scale, as assessed by blinded colonoscopists.

The Prepopik regimen of one-half packet administered as two doses did not demonstrate comparable efficacy to the comparator, PEG, in patients 9 to 12 years of age and is not a recommended dosage regimen [see Dosage and Administration (2)].

The Prepopik regimen of one packet administered as two doses demonstrated successful colon cleansing in both the 9 to 12 year age group and the 13 to 16 year age group. The efficacy rates were similar to those observed in the PEG groups, as shown in Table 5.

How Supplied

Prepopik is supplied in a carton containing 2 packets, each holding 16.1 grams of powder in orange flavor or 16.2 grams of powder in cranberry flavor for oral solution, along with a pre-marked dosing cup. Each packet for both flavors contains 10 mg sodium picosulfate, 3.5 g magnesium oxide and 12 g anhydrous citric acid. The excipients for both flavors include potassium hydrogen carbonate, sodium saccharin, orange or cranberry flavor. The orange flavor contains acacia gum, lactose, ascorbic acid, and butylated hydroxyanisole, and the cranberry flavor contains maltodextrin, glyceryl triacetate (triacetin) and sodium octenyl succinated starch.

Storage

Store at room temperature between 20 to 25°C (68 to 77°F). Excursions permitted between 15° and 30°C (59° and 86° F) [see USP Controlled room temperature].

Orange flavor:

NDC# 55566-9300-2 Kit, 2 packets and cup

Cranberry flavor:

NDC# 55566-9700-1- Kit, 2 packets and cup